KR20210025089A - (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl )-1H-pyrazole-4-carboxamide spray-dried dispersions and formulations - Google Patents

Abstract

(S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl )-1H-pyrazole-4-carboxamide, a pharmaceutically acceptable salt or combination thereof, spray-dried dispersions and pharmaceutical compositions, and spray-dried dispersions in the treatment of cancer and autoimmune and inflammatory diseases The use of water and pharmaceutical compositions is disclosed. (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1, which is also useful in the treatment of cancer and autoimmune and inflammatory diseases Crystalline forms of 1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide are also provided.

Description

(S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl )-1H-pyrazole-4-carboxamide spray-dried dispersions and formulations

The present disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion (SDD) thereof, or a pharmaceutical composition thereof. More specifically, it relates to compositions of compounds of formula (I) useful for the treatment and prevention of diseases that can be treated with BTK inhibitors, including BTK-associated diseases and disorders.

BTK is a cytoplasmic, non-receptor tyrosine kinase belonging to the Tec family kinases (Herman, S.E.M. et al., Blood. 2011, 117(23): 6287-6296). The structure of BTK consists of several domains: an N-terminal plextrin homology (PH) domain, a proline-rich TEC homology domain, two SRC homology domains (SH3 followed by SH2) and a C-terminal kinase domain (BTK-KD). (Marcotte, DJ et al., Protein Sci. 2010, 19(3): 429-439).

BTK is expressed in hematopoietic cells, excluding T cells and plasma cells, and is involved in all aspects of B-cell development, including proliferation, maturation, differentiation, apoptosis, and cell migration (Wu J., et al., J Hematol Oncol. 2016; 9: 80). BTK is also expressed on certain bone marrow cells, including monocytes/macrophages, neutrophils and mast cells. In these bone marrow cells, BTK appeared upon immune complex-mediated activation of FcγR and FcεR, which may contribute to the pathogenesis of rheumatoid arthritis (Whang 2014). BTK is also required for the maturation of osteoclasts, so inhibition of BTK can prevent bone erosion associated with rheumatoid arthritis.

PIP3 (phosphatidylinositol-3,4,5-triphosphate) production and binding of BTK to the PH domain and phosphorylation of Tyr-551 of BTK by Src family kinases stimulate the membrane localization and activation of BTK. Activation of BTK ^{leads to Ca 2+} recruitment and activation of NF-κB and MAP (mitogen-activated protein) kinase pathways (Honigberg et al. Proc. Natl. Acad. Sci. USA 2010 Jul 20; 107(29)) : 13075-13080).

Abnormal BTK expression and/or activity has been demonstrated in different cancers and autoimmune disorders.

Examples of BTK inhibitors are disclosed in WO17/103661.

There is a need to provide improved formulations for BTK inhibitors, especially those exhibiting low solubility. Additionally, there is a need to provide agents that increase plasma concentrations of BTK inhibitors and/or provide consistent plasma concentrations. The present invention provides a variety of formulations that address one or more of these needs.

In one form, the invention relates to a compound of formula (I) present in an amount from about 5% w/w to about 30% w/w; HPMCAS polymer present in an amount from about 5% w/w to about 30% w/w; Microcrystalline cellulose present in an amount from about 30% w/w to about 60% w/w; Mannitol or lactose monohydrate, or a combination thereof, present in a total amount of about 10% w/w to about 60% w/w; Sodium starch glycolate or croscarmellose sodium or a combination thereof present in a total amount of about 0.5% w/w to about 5% w/w; And magnesium stearate present in an amount of about 0.05% w/w to about 2% w/w; And, optionally, silicon dioxide, if present, in an amount of about 0.3% w/w to about 0.6% w/w, wherein the total is 100% or less.

In one form, the invention relates to a compound of formula (I) present in an amount from about 5% w/w to about 30% w/w; HPMCAS polymer present in an amount from about 5% w/w to about 30% w/w; Microcrystalline cellulose present in an amount from about 30% w/w to about 60% w/w; Mannitol or lactose monohydrate, or a combination thereof, present in a total amount of about 10% w/w to about 60% w/w; Sodium starch glycolate or croscarmellose sodium or a combination thereof present in a total amount of about 0.5% w/w to about 5% w/w; And magnesium stearate present in an amount of about 0.05% w/w to about 2% w/w; And, optionally, silicon dioxide, if present, in an amount of about 0.3% w/w to about 0.6% w/w, wherein the total is 100% or less.

In one form, the invention relates to a compound of formula (I) present in an amount from about 5% w/w to about 30% w/w; HPMCAS polymer present in an amount from about 5% w/w to about 30% w/w; Microcrystalline cellulose present in an amount from about 30% w/w to about 60% w/w; Lactose monohydrate present in an amount from about 10% w/w to about 60% w/w; Croscarmellose sodium present in a total amount of about 0.5% w/w to about 5% w/w; And magnesium stearate present in an amount of about 0.05% w/w to about 2% w/w; And silicon dioxide, if present, in an amount of about 0.3% w/w to about 0.6% w/w, wherein the total is 100% or less.

In one embodiment, the ratio of the compound of formula (I) to the HPMCAS polymer is from about 1:4 to about 4:1. In another embodiment, the ratio of compound of formula (I) to HPMCAS polymer is about 1:1.

In yet another aspect, the invention relates to a compound of formula (I) present in an amount from about 21% w/w to about 23% w/w; HPMCAS polymer present in an amount from about 21% w/w to about 23% w/w; Microcrystalline cellulose present in an amount from about 38% w/w to about 39% w/w; Mannitol present in an amount from about 12% w/w to about 13% w/w; Sodium starch glycolate present in an amount from about 4% w/w to about 6% w/w; And magnesium stearate present in an amount of about 0.4% w/w to about 0.6% w/w, wherein the total is 100% w/w or less.

In yet another aspect, the invention relates to a compound of formula (I) present in an amount from about 21% w/w to about 23% w/w; HPMCAS polymer present in an amount from about 21% w/w to about 23% w/w; Microcrystalline cellulose present in an amount from about 33% w/w to about 34% w/w; Lactose monohydrate present in an amount from about 16% w/w to about 17% w/w; Croscarmellose sodium present in an amount from about 2% w/w to about 6% w/w; Magnesium stearate present in an amount from about 0.4% w/w to about 0.6% w/w; And silicon dioxide present in an amount of about 0.4% w/w to about 0.6% w/w, wherein the total is 100% or less.

In yet another aspect, the invention relates to a compound of formula (I) present in an amount from about 21% w/w to about 23% w/w; HPMCAS polymer present in an amount from about 21% w/w to about 23% w/w; Microcrystalline cellulose present in an amount from about 25% w/w to about 26% w/w; Mannitol present in an amount from about 25% w/w to about 26% w/w; Sodium starch glycolate present in an amount from about 4% w/w to about 6% w/w; And magnesium stearate present in an amount of about 0.4% w/w to about 0.6% w/w, wherein the total is 100% w/w or less.

In yet another aspect, the invention relates to a compound of formula (I) present in an amount of about 8% w/w; HPMCAS polymer present in an amount of about 8% w/w; Microcrystalline cellulose present in an amount of about 40% w/w; Mannitol present in an amount of about 40% w/w; Sodium starch glycolate present in an amount of about 3.5% w/w; And magnesium stearate present in an amount of about 0.3% w/w.

In one embodiment, the pharmaceutical composition as described above is formulated as a tablet. In another embodiment, the pharmaceutical composition comprises about 25 mg to about 220 mg of a compound of formula I. In another embodiment, the pharmaceutical composition comprises a compound of formula I in an amount selected from one of the following: about 25 mg, about 50 mg and about 100 mg.

In another form, the present invention provides a method of treating BTK-associated cancer in a subject in need thereof, comprising administering to the subject a pharmaceutical composition as described above. In one embodiment, the BTK associated cancer is selected from mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstrom macroglobulinemia, and marginal zone lymphoma.

In yet another aspect, the present invention provides a method of treating cancer in a subject in need thereof. The method comprises administering to the subject a compound of formula I in a dose of about 20 mg to about 120 mg. The cancer is selected from the following cancers: mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstrom macroglobulinemia and marginal zone lymphoma. In certain embodiments, the dose is selected from one of the following: about 25 mg, about 50 mg and about 100 mg.

In another embodiment, the present invention provides a BTK selected from mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstrom macroglobulinemia, and marginal zone lymphoma, wherein the compound of formula I is administered in a dose of about 20 mg to 120 mg. -Provides the use of a pharmaceutical composition as described above for the treatment of associated cancer. In certain embodiments, the dosage at which the compound of formula I is administered is selected from about 25 mg, about 50 mg and about 100 mg.

In another form, the present invention provides a pharmaceutical composition as described above for use in the treatment of a BTK-associated cancer selected from mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstrom macroglobulinemia and marginal zone lymphoma. do. In certain embodiments, the compound of formula I is administered at a dose selected from one of the following: about 25 mg, about 50 mg, and about 100 mg.

In another form, the present invention provides compounds of formula I in spray-dried dispersions or pharmaceutical compositions useful for the treatment and prevention of diseases that can be treated with BTK inhibitors, including BTK-associated diseases and disorders.

Accordingly, provided herein are spray-dried dispersions comprising a compound of formula I and a hypromellose acetate succinate (HPMCAS) polymer.

In some embodiments, the ratio of the compound of Formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof to the HPMCAS polymer is from about 1:4 to about 4:1. In some embodiments, the ratio of the compound of Formula I to the HPMCAS polymer is about 1:1. In some embodiments, the HPMCAS polymer is HPMCAS-MG.

Also provided herein is a method of preparing a spray-dried dispersion in which a compound of formula (I) is dissolved in one or more organic solvents and then spray-dried. In some embodiments, spraying after dissolving a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof in dichloromethane:methanol, preferably in a dichloromethane:methanol ratio of about 80:20 wt/wt. -Dry. In another embodiment, the compound of formula I is dissolved in methanol. In another embodiment, Form A of the compound of formula (I) is dissolved in one or more organic solvents.

A first composition comprising a spray-dried dispersion and one or more pharmaceutical excipients, wherein the spray-dried dispersion is a HPMCAS polymer and a compound of formula I or a pharmaceutically acceptable salt thereof, in amorphous or polymorphic form Also provided herein is a pharmaceutical composition comprising a.

In some embodiments, the ratio of the compound of Formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof to the HPMCAS polymer in the spray-dried dispersion is from about 1:4 to about 4:1. In some embodiments, the ratio of the compound of Formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof to the HPMCAS polymer in the spray-dried dispersion is about 1:1. In some embodiments, the HPMCAS polymer is HPMCAS-MG.

In some embodiments, the spray-dried dispersion is present in an amount of about 20% to about 75% w/w of the first composition. In some embodiments, the spray-dried dispersion is present in an amount of about 30% to about 60% w/w of the first composition. In some embodiments, the spray-dried dispersion is present in an amount of about 40% to about 50% w/w of the first composition. In some embodiments, the spray-dried dispersion is present in an amount of about 45% w/w of the first composition.

In some embodiments, the pharmaceutical excipient is selected from the group consisting of fillers, lubricants, and combinations thereof.

In some embodiments, the filler is present in an amount of about 25% to about 80% w/w of the first composition. In some embodiments, the filler is present in an amount of about 45% to about 65% w/w of the first composition. In some embodiments, the filler is present in an amount of about 55% w/w of the first composition.

In some embodiments, the filler is selected from the group consisting of saccharides, gelatin, synthetic polymers, or combinations thereof. In some embodiments, the filler is sucrose, lactose, microcrystalline cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, starch, xylitol, sorbitol, mannitol, polyvinylpyrrolidone, polyethylene. Glycol, polyvinyl alcohol, polymethacrylate, poloxamer, magnesium stearate, calcium stearate, sodium stearate, stearic acid, hydrogenated vegetable oil, mineral oil, sodium lauryl sulfate, magnesium lauryl sulfate, glyceryl Palmitostearate, sodium benzoate, sodium stearyl fumarate, colloidal silicon dioxide, sodium benzoate, sodium oleate, sodium acetate and combinations thereof.

In some embodiments, the filler is a binder, a disintegrant, or a combination thereof.

In some embodiments, the binder is present in an amount of about 30% to about 80% w/w of the first composition. In some embodiments, the binder is present in an amount of about 40% to about 60% w/w of the first composition. In some embodiments, the binder is present in an amount of about 52% w/w of the first composition.

In some embodiments, the binder is microcrystalline cellulose, cellulose ether, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxy methyl cellulose starch, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, mannitol, xylitol, sorbitol , Lactose, sucrose, sorbitol, gelatin, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, polymethacrylate, and combinations thereof.

In some embodiments, the binder is microcrystalline cellulose, mannitol, or a combination thereof.

In some embodiments, microcrystalline cellulose is present in an amount of about 5% to about 55% w/w of the first composition. In some embodiments, microcrystalline cellulose is present in an amount of about 10% to about 40% w/w of the first composition. In some embodiments, microcrystalline cellulose is present in an amount of about 20% to about 30% w/w of the first composition. In some embodiments, microcrystalline cellulose is present in an amount of about 30% to about 60% w/w of the first composition. In some embodiments, microcrystalline cellulose is present in an amount of about 26% w/w of the first composition.

In some embodiments, mannitol is present in an amount of about 5% to about 55% w/w of the first composition. In some embodiments, mannitol is present in an amount of about 10% to about 40% w/w of the first composition. In some embodiments, mannitol is present in an amount of about 20% to about 30% w/w of the first composition. In some embodiments, mannitol is present in an amount of about 26% w/w of the first composition.

In some embodiments, the disintegrant is present in an amount of about 0.5% to about 5% w/w of the first composition. In some embodiments, the disintegrant is present in an amount of about 1.5% to about 3.5% w/w of the first composition. In some embodiments, the disintegrant is present in an amount of about 2.5% w/w of the first composition.

In some embodiments, the disintegrant is selected from the group consisting of sodium starch glycolate, alginic acid, sodium alginate, croscarmellose sodium, ion exchange resins, and combinations thereof. In some embodiments, the disintegrant is sodium starch glycolate.

In some embodiments, the lubricant is present in an amount of about 0.05% to about 2.5% w/w of the first composition. In some embodiments, the lubricant is present in an amount of about 0.1% to about 1% w/w of the first composition. In some embodiments, the lubricant is present in an amount of about 0.25% w/w of the first composition.

In some embodiments, the lubricant is magnesium stearate, calcium stearate, sodium stearate, stearic acid, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulfate, glyceryl palmitostearate. , Sodium benzoate, sodium stearyl fumarate, colloidal silicon dioxide, sodium benzoate, sodium oleate, sodium acetate, and combinations thereof. In some embodiments, the lubricant is magnesium stearate.

In some embodiments, the spray-dried dispersion is present in an amount of about 20% to about 75% w/w of the first composition, and the filler is in an amount of about 25% to about 80% w/w of the first composition. And the lubricant is present in an amount of about 0.05% to about 2% w/w of the first composition.

In some embodiments, the spray-dried dispersion is present in an amount of about 45% w/w of the first composition, the filler is present in an amount of about 55% w/w of the first composition, and the lubricant is It is present in an amount of about 0.25% w/w of the composition.

In some embodiments, the spray-dried dispersion is present in an amount of about 40% to about 50% w/w of the first composition, and the microcrystalline cellulose is about 20% to about 30% w/w of the first composition. And mannitol is present in an amount of about 20% to about 30% w/w of the first composition, and sodium starch glycolate is present in an amount of about 0.5% to about 5% w/w of the first composition. And magnesium stearate is present in an amount of about 0.05% to about 2% w/w of the first composition.

In some embodiments, the spray-dried dispersion and pharmaceutical excipient are blended. In some embodiments, the first composition is granulated. In some embodiments, the first composition is granulated by roller compaction.

Pharmaceutical compositions comprising a first composition and one or more pharmaceutical excipients are also provided herein.

In some embodiments, the first composition is present in an amount of about 15% to about 99% w/w of the total composition.

In some embodiments, the one or more pharmaceutical excipients are selected from the group consisting of fillers, lubricants, and combinations thereof.

In some embodiments, the lubricant is present in an amount of about 0.05% to about 2% w/w of the total composition. In some embodiments, the lubricant is present in an amount of about 0.1% to about 1.0% w/w of the total composition. In other embodiments, the lubricant is present in an amount of about 0.1% to about 0.8% w/w of the total composition. In other embodiments, the lubricant is present in an amount of about 0.4% to about 0.6% w/w of the total composition. In another embodiment, the lubricant is present in an amount of about 0.3% w/w of the total composition.

In some embodiments, the lubricant is magnesium stearate, calcium stearate, sodium stearate, stearic acid, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulfate, glyceryl palmitostearate. , Sodium benzoate, sodium stearyl fumarate, colloidal silicon dioxide, sodium benzoate, sodium oleate, sodium acetate, and combinations thereof. In some embodiments, the lubricant is magnesium stearate.

In some embodiments, the filler is present in an amount of about 1% to about 85% w/w of the total composition.

In some embodiments, the filler is sucrose, lactose, microcrystalline cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, starch, xylitol, sorbitol, mannitol, polyvinylpyrrolidone, polyethylene. Glycol, polyvinyl alcohol, polymethacrylate, poloxamer, magnesium stearate, calcium stearate, sodium stearate, stearic acid, hydrogenated vegetable oil, mineral oil, sodium lauryl sulfate, magnesium lauryl sulfate, glyceryl Palmitostearate, sodium benzoate, sodium stearyl fumarate, colloidal silicon dioxide, sodium benzoate, sodium oleate, sodium acetate and combinations thereof.

In some embodiments, the filler is a binder, a disintegrant, or a combination thereof.

In some embodiments, the disintegrant is present in an amount of about 0.5% to about 5% w/w of the total composition. In some embodiments, the disintegrant is present in an amount of about 4% to about 6% w/w of the total composition. In some embodiments, the disintegrant is present in an amount of about 2.5% w/w of the total composition.

In some embodiments, the disintegrant is selected from the group consisting of sodium starch glycolate, alginic acid, sodium alginate, croscarmellose sodium anion exchange resin, and combinations thereof. In some embodiments, the disintegrant is sodium starch glycolate.

In some embodiments, the first composition is present in an amount of about 90% to about 99% w/w of the total composition. In some embodiments, the first composition is present in an amount of about 97% w/w of the total composition.

In some embodiments, the first composition is present in an amount of about 15% to about 60% w/w of the total composition. In some embodiments, the first composition is present in an amount of about 30% to about 40% w/w of the total composition. In some embodiments, the first composition is present in an amount of about 35% w/w of the total composition.

In some embodiments, the binder is present in an amount of about 40% to about 85% w/w of the total composition. In some embodiments, the binder is present in an amount of about 55% to about 75% w/w of the total composition.

In some embodiments, the binder is microcrystalline cellulose, cellulose ether, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxy methyl cellulose starch, cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, mannitol, xylitol, Sorbitol, lactose, sucrose, sorbitol, gelatin, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, polymethacrylate, and combinations thereof.

In some embodiments, the binder is microcrystalline cellulose, mannitol, or a combination thereof.

In some embodiments, microcrystalline cellulose is present in an amount of about 25% to about 35% w/w of the total composition. In some embodiments, microcrystalline cellulose is present in an amount of about 31% w/w of the total composition.

In some embodiments, mannitol is present in an amount of about 25% to about 35% w/w of the total composition. In some embodiments, mannitol is present in an amount of about 31% w/w of the total composition.

In some embodiments, the first composition is blended with a pharmaceutical excipient. In some embodiments, the pharmaceutical composition is co-milled.

In some embodiments, the pharmaceutical composition is formulated as a tablet. In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, is present in an amount of about 10 mg to about 50 mg. In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, is in an amount of about 25 mg to about 220 mg, more preferably in an amount of about 50 mg to about 150 mg, more More preferably in an amount of about 80 mg to about 120 mg, and in an even more preferred embodiment in an amount of about 100 mg.

Pharmaceutical compositions comprising the following are also provided herein:

(S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl )-1H-pyrazole-4-carboxamide;

HPMCAS polymer; And

One or more pharmaceutical excipients.

In some embodiments, the HPMCAS polymer is HPMCAS-MG.

In some embodiments, the one or more pharmaceutical excipients are selected from the group consisting of fillers, lubricants, and combinations thereof.

In some embodiments, the filler is sucrose, lactose, microcrystalline cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, starch, xylitol, sorbitol, mannitol, polyvinylpyrrolidone, polyethylene. Glycol, polyvinyl alcohol, polymethacrylate, magnesium stearate, calcium stearate, sodium stearate, stearic acid, hydrogenated vegetable oil, mineral oil, sodium lauryl sulfate, magnesium lauryl sulfate, glyceryl palmitostea Rate, sodium benzoate, sodium stearyl fumarate, colloidal silicon dioxide, sodium benzoate, sodium oleate, sodium acetate, and combinations thereof.

In some embodiments, the lubricant is magnesium stearate, calcium stearate, sodium stearate, stearic acid, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulfate, glyceryl palmitostearate. , Sodium benzoate, sodium stearyl fumarate, colloidal silicon dioxide, sodium benzoate, sodium oleate, sodium acetate, and combinations thereof.

In some embodiments, the composition comprises:

(S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl )-1H-pyrazole-4-carboxamide;

HPMCAS polymer;

Microcrystalline cellulose;

Mannitol;

Sodium starch glycolate; And

Magnesium stearate.

In some embodiments, the composition comprises:

(S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)- present in an amount of about 5% to about 30% w/w of the composition 1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide;

HPMCAS polymer present in an amount from about 5% to about 30% w/w of the composition;

Microcrystalline cellulose present in an amount from about 30% to about 60% w/w of the composition;

Mannitol present in an amount from about 30% to about 60% w/w of the composition;

Sodium starch glycolate present in an amount from about 0.5% to about 5% w/w of the composition; And

Magnesium stearate present in an amount from about 0.05% to about 2% w/w of the composition.

In some embodiments, the composition comprises:

(S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1 present in an amount of about 8% w/w of the composition ,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide;

HPMCAS polymer present in an amount of about 8% w/w of the composition;

Microcrystalline cellulose present in an amount of about 40% w/w of the composition;

Mannitol present in an amount of about 40% w/w of the composition;

Sodium starch glycolate present in an amount of about 3.5% w/w of the composition; And

Magnesium stearate present in an amount of about 0.3% w/w of the composition.

In some embodiments, the composition comprises:

(S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)- present in an amount of about 10% to about 30% w/w of the composition 1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide;

HPMCAS polymer present in an amount from about 10% to about 30% w/w of the composition;

Microcrystalline cellulose present in an amount from about 20% to about 30% w/w of the composition;

Mannitol present in an amount from about 20% to about 30% w/w of the composition;

Sodium starch glycolate present in an amount from about 2% to about 8% w/w of the composition; And

Magnesium stearate present in an amount from about 0.05% to about 2% w/w of the composition.

In some embodiments, a composition herein comprises:

(S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1 present in an amount of about 22% w/w of the composition ,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide;

HPMCAS polymer present in an amount of about 22% w/w of the composition;

Microcrystalline cellulose present in an amount of about 25% w/w of the composition;

Mannitol present in an amount of about 25% w/w of the composition;

Sodium starch glycolate present in an amount of about 5% w/w of the composition; And

Magnesium stearate present in an amount of about 0.5% w/w of the composition.

In some embodiments, the HPMCAS polymer is HPMCAS-MG.

In some embodiments, the pharmaceutical composition is formulated as a tablet. In some embodiments, the tablet is coated.

Also provided herein is a method of making a pharmaceutical composition, comprising:

(S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl )-1H-pyrazole-4-carboxamide, HPMCAS polymer and organic solvent are mixed to form a mixture;

Spray-drying the mixture to form a spray-dried dispersion; And

Granulating the spray-dried dispersion to form a first composition.

In some embodiments, the organic solvent is a mixture of dichloromethane and methanol. In some embodiments, the organic solvent is 80:20 dichloromethane:methanol. In some embodiments, the spray-dried dispersion is granulated after blending with one or more pharmaceutical excipients. In some embodiments, the spray-dried dispersion is granulated after drying in an oven. In some embodiments, the spray-dried dispersion is granulated after blending with one or more pharmaceutical excipients. In some embodiments, the spray-dried dispersion is granulated by roller compaction. In some embodiments, the first composition is blended with one or more pharmaceutical excipients. In some embodiments, the first composition is co-milled. In some embodiments, the first composition is pressed into tablets. In some embodiments, the tablet is coated. In some embodiments, the coating includes a polymer, plasticizer, pigment, or combinations thereof.

In some embodiments, (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1, in a spray-dried dispersion The ratio of 1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide to HPMCAS polymer is from about 1:4 to about 4:1. In some embodiments, (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1, in a spray-dried dispersion The ratio of 1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide to HPMCAS polymer is about 1:1. In some embodiments, the HPMCAS polymer is HPMCAS-MG.

Also provided herein are crystalline forms of compounds of formula (I) having the formula:

Also provided herein is Form A of a compound of formula (I) characterized by having an X-ray powder diffraction (XRPD) pattern comprising peaks at °2θ values of 15.8±0.2, 16.2±0.2, and 11.9±0.2.

Form A of a compound of formula I characterized by having an X-ray powder diffraction (XRPD) pattern comprising peaks at °2θ values of 15.8±0.2, 16.2±0.2, 11.9±0.2, 19.0±0.2, and 18.3±0.2. Is also provided herein.

Characterized by having an X-ray powder diffraction (XRPD) pattern including peaks at °2θ values of 15.8±0.2, 16.2±0.2, 11.9±0.2, 19.0±0.2, 18.3±0.2, 23.8±0.2, and 20.5±0.2. Form A of a compound of formula I is also provided herein.

X containing peaks at °2θ values of 15.8±0.2, 16.2±0.2, 11.9±0.2, 19.0±0.2, 18.3±0.2, 23.8±0.2, 20.5±0.2, 25.7±0.2, 20.1±0.2, and 9.5±0.2 Also provided herein is Form A of a compound of formula I characterized by having a line powder diffraction (XRPD) pattern.

°2θ of 15.8±0.2, 16.2±0.2, 11.9±0.2, 19.0±0.2, 18.3±0.2, 23.8±0.2, 20.5±0.2, 25.7±0.2, 20.1±0.2, 9.5±0.2, 25.0±0.2, and 11.1±0.2 Also provided herein is Form A of a compound of formula (I) characterized by having an X-ray powder diffraction (XRPD) pattern comprising peaks in values.

Also provided herein is Form A of a compound of Formula I having an XRPD pattern substantially as shown in FIG. 4A.

Also provided herein is Form A of a compound of Formula I having a differential scanning calorimetry (DSC) curve comprising an endotherm having an onset temperature of about 185°C.

Also provided herein is Form A of a compound of Formula I having a DSC thermogram substantially as shown in FIG. 4C.

Also provided herein is a solid oral pharmaceutical composition comprising a pharmaceutical excipient and a crystalline form of a compound of formula (I).

Also provided herein are solid oral pharmaceutical compositions prepared by mixing a crystalline form of a compound of formula I and a pharmaceutical excipient.

Also provided herein is a method of preparing a solid oral pharmaceutical composition comprising the step of mixing a crystalline form of a compound of formula (I) and a pharmaceutical excipient.

Also provided herein is a method of treating cancer in a subject in need thereof comprising administering a spray-dried dispersion, pharmaceutical composition or a therapeutically effective amount of a compound of formula I. In some embodiments, the cancer is a BTK-associated cancer.

Also provided herein is a method of treating cancer in a subject in need thereof, comprising:

(a) detecting a dysregulation of the expression or activity or level of a BTK gene, a BTK kinase, or any of these; And

(b) administering to the subject a compound of formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof.

Comprising the step of administering to a subject identified or diagnosed as having BTK-associated cancer a compound of formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form, a spray-dried dispersion thereof, or a pharmaceutical composition thereof, Also provided herein are methods of treating BTK-associated cancer in a subject.

Also provided herein is a method of treating a BTK-associated cancer in a subject, comprising:

Detecting a dysregulation of the expression or activity or level of a BTK gene, a BTK kinase, or any of these; And

Administering to a subject determined to have BTK-associated cancer a compound of formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof.

A compound of formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, to a subject having a clinical record indicating that the subject has a dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of these, Also provided herein is a method of treating a subject comprising administering a spray-dried dispersion thereof or a pharmaceutical composition thereof.

The subject comprising administering to a subject in need thereof a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form, a spray-dried dispersion thereof, or a pharmaceutical composition thereof to a subject in need thereof. Also provided herein are methods of inhibiting metastasis of cancer in.

In some embodiments, the cancer is a BTK-associated cancer.

In some embodiments, a compound of Formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof is used in combination with another chemotherapeutic agent.

Treatment comprising administration of a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form, spray-dried dispersion thereof or a pharmaceutical composition thereof for a subject identified or diagnosed with BTK-associated cancer Also provided herein is a method of selecting a treatment for a subject, comprising the step of selecting.

Also provided herein is a method of selecting a treatment for a subject having cancer, comprising:

Detecting a dysregulation of the expression or activity or level of a BTK gene, a BTK kinase, or any of these in the subject; And

Selecting a treatment comprising administration of a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof for a subject.

Also herein is a method of selecting a subject for treatment comprising administration of a compound of formula (I) or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical composition thereof, comprising: Provided in:

Identifying a subject with BTK-associated cancer; And

Selecting a subject for treatment comprising administration of a compound of formula (I) or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof.

A method of selecting a subject with cancer for treatment comprising administration of a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical composition thereof, comprising This is also provided herein:

Detecting a dysregulation of the expression or activity or level of a BTK gene, a BTK kinase, or any of these in the subject; And

Selecting a subject for treatment comprising administration of a compound of formula (I) or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof.

In some embodiments, the step of determining whether the cancer in the subject is a BTK-associated cancer is an assay that detects dysregulation in the expression or activity or level of the BTK gene, BTK kinase protein, or any of them in a sample from the subject. And performing. In some embodiments, the method further comprises obtaining a sample from the subject. In some embodiments, the sample is a biopsy sample. In some embodiments, the assay is selected from the group consisting of sequencing, immunohistochemistry, immunoblot, enzyme-linked immunosorbent assay, and fluorescence in situ hybridization (FISH). In some embodiments, the FISH is a degraded FISH assay. In some embodiments, sequencing is pyrosequencing or next-generation sequencing.

In some embodiments, the dysregulation in the expression or activity or level of the BTK gene, BTK kinase protein, or any of these is a BCR signaling pathway gene, a BCR (cleavage point cluster protein) signaling pathway protein, or any one of these. It is the result of dysregulation at the expression or activity or level of.

In some embodiments, the BCR signaling pathway gene or BCR signaling pathway protein is selected from the group consisting of Cyclin-D1, CARD11, CD79B, CD79A, MYD88, and combinations thereof.

In some embodiments, the dysregulation in the expression or activity or level of a BCR signaling pathway gene, a BCR signaling pathway protein, or any one of them is the result of one or more genetic alterations.

In some embodiments, the one or more genetic alterations consist of chromosomal translocation t(11;14)(q13;q32), deletion of chromosome region 17p13, deletion of chromosome region 11q23, deletion of chromosome region 13q14, and trisomy of chromosome 12. Is selected from the group.

In some embodiments, the one or more genetic alterations are one or more point mutations in a gene encoding a BCR signaling pathway protein.

In some embodiments, one or more point mutations in a gene encoding a BCR signaling pathway protein results in translation of a BCR signaling pathway protein having one or more amino acid substitutions, wherein the BCR signaling pathway protein is CARD11, CD79B, CD79A, MYD88 and combinations thereof. In some embodiments, BCR signaling pathway protein with one or more point mutations to the amino acid positions in the genes encoding: MYD88 results in a translation of BCR signaling pathway protein comprising the amino acid substitution at least one of the at least one of ^L265 . In some embodiments, the amino acid substitution is MYD88 ^L265P .

In some embodiments, the dysregulation in the expression or activity or level of the BTK gene, BTK kinase protein, or any of these is one or more point mutations in the BTK gene. In some embodiments, the one or more point mutations in the BTK gene are translation of a BTK protein having one or more amino acid substitutions at one or more of the following amino acid positions: 117, 316, 474, 481, 528, 560, 562, and 601 Causes. In some embodiments, the one or more point mutations in the BTK gene are one of the following amino acid substitutions: T117P, T316A, T474I, T474M, T474S, C481S, C481F, C481T, C481G, C481R, L528W, P560L, R562W, R562G, and F601L. Induces the translation of the abnormal BTK protein.

Also provided herein is a method of treating cancer in a subject in need thereof, comprising:

(a) detecting a dysregulation of the expression or activity or level of a BCR signaling pathway gene, a BCR signaling pathway protein, or any of these; And

(b) administering to the subject a compound of formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof.

A compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject having a clinical record indicating that the subject has dysregulation of the expression or activity or level of the BCR signaling pathway gene, the BCR signaling pathway protein, or any of these, Also provided herein is a method of treating a subject comprising administering an amorphous or polymorphic form, a spray-dried dispersion thereof, or a pharmaceutical composition thereof.

In some embodiments, the BTK-associated cancer is Hodgkin's lymphoma, diffuse large B cell lymphoma (DLBCL) (e.g., activated B cell-like DLBCL (ABC-DLBCL)), follicular lymphoma, mantle cell lymphoma, marginal zone Lymphoma (e.g., extranodal marginal B-cell lymphoma, splenic marginal lymphoma), Burkitt's lymphoma, Waldenstrom's macroglobulinemia (lymphocyte lymphoma (LPL)), primary central nervous system lymphoma, small lymphocytic lymphoma, chronic lymphocytic Leukemia (CLL), acute lymphocytic leukemia (ALL), B-cell prolymphocytic leukemia, precursor B-lymphoblastic leukemia, hairy cell leukemia, acute myelogenous leukemia (AML), chronic myelogenous leukemia, multiple myeloma, plasma cells Myeloma, plasmacytoma, bone cancer, bone metastasis, breast cancer, gastroesophageal cancer, pancreatic cancer, ovarian cancer, prostate cancer, lung cancer, colon cancer, uterine cancer, hepatocellular cancer, head and neck cancer, or glioma.

In some embodiments, the BTK-associated cancer is a hematological cancer. In some embodiments, the blood cancer is selected from the group consisting of leukemia, lymphoma (non-Hodgkin's lymphoma), Hodgkin's disease, and myeloma.

In some embodiments, the blood cancer is acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myelocytic leukemia (CML). Sexual leukemia (CMML), chronic neutrophilic leukemia (CNL), acute undifferentiated leukemia (AUL), anaplastic large cell lymphoma (ALCL), prolymphocytic leukemia (PML), childhood myelomonocytic leukemia (JMML), adult T- Cell ALL, AML with line 3 myelodysplasia (AML/TMDS), mixed line leukemia (MLL), myelodysplastic syndrome (MDS), myeloproliferative disorder (MPD), diffuse versus B cell lymphoma (DLBCL) (e.g., Activated B cell-like DLBCL (ABC-DLBCL)), follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma (e.g., extranodal marginal zone B-cell lymphoma, spleen marginal zone lymphoma), Burkitt's lymphoma, Waldenstrom macroglobulinemia ( Lymphoblastic lymphoma (LPL)), primary central nervous system lymphoma, small lymphocytic lymphoma, precursor B-lymphoblastic leukemia, hairy cell leukemia, chronic myelogenous leukemia, anaplastic large cell lymphoma, MALT lymphoma, plasma cell myeloma, Plasmacytoma and multiple myeloma (MM).

In some embodiments, the BTK-associated cancer is a B-cell malignancy. In some embodiments, the B-cell malignancies are Hodgkin's lymphoma, diffuse large B cell lymphoma (DLBCL) (e.g., activated B cell-like DLBCL (ABC-DLBCL)), follicular lymphoma, mantle cell lymphoma, Marginal zone lymphoma (e.g., extranodal marginal B-cell lymphoma, splenic marginal zone lymphoma), Burkitt's lymphoma, Waldenstrom macroglobulinemia (Lymphplasmocytic lymphoma (LPL)), primary central nervous system lymphoma, small lymphocytic lymphoma, chronic lymph Constituent leukemia, acute lymphoblastic leukemia (ALL), B-cell prolymphocytic leukemia, precursor B-lymphoblastic leukemia or hairy cell leukemia.

In some embodiments, the BTK-associated cancer is selected from the group consisting of mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstrom macroglobulinemia, and marginal zone lymphoma.

In some embodiments, the BTK-associated cancer has not undergone transformation. Non-limiting examples of transformations in BTK-associated cancers include Richter transformation, prolymphocyte transformation (e.g., prolymphocyte transformation of CLL), transformed non-Hodgkin's lymphoma and blastoid lymphoma (e.g. For example, blastoid variant mantle cell lymphoma).

In some embodiments, the BTK-associated cancer is not a cancer with known central nervous system involvement by lymphoma.

In some embodiments, the BTK-associated cancer is a solid tumor.

In some embodiments, the solid tumor is selected from the group consisting of bone cancer, bone metastasis, breast cancer, gastroesophageal cancer, pancreatic cancer, ovarian cancer, prostate cancer, lung cancer, colon cancer, uterine cancer, hepatocellular cancer, head and neck cancer, and glioma.

In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof is administered orally.

In some embodiments, the method further comprises administering to the subject an additional therapy or therapeutic agent.

In some embodiments, the additional therapy or therapeutic agent is from the group consisting of radiotherapy, cytotoxic chemotherapeutic agents, kinase-targeting therapy, apoptosis modulators, signal transduction inhibitors, immune-targeting therapy, transcriptional control inhibitors, and angiogenesis-targeting therapy. Is selected. In some embodiments, the additional therapeutic agent is selected from one or more kinase-targeted therapeutic agents. In some embodiments, the kinase-targeting therapeutic agent targets a kinase from a kinase family selected from JAK, Src, IRAK, and combinations thereof.

In some embodiments, the additional therapeutic agent is selected from one or more protein inhibitors. In some embodiments, the one or more protein inhibitors are from the group consisting of anti-apoptotic proteins, heat shock proteins, nuclear efflux proteins, kinases, histone deacetylases, E3 ubiquitin ligase, histone-lysine N-methyltransferases, and combinations thereof. Inhibits the selected protein. In some embodiments, the one or more protein inhibitors are PI3K, JAK-2, IRAK1, IRAK4, BMX, TAK1, Src family, HDAC6, MDM2, BCL-2, EZH2, EHMT2, PIM, JAK3, mTOR, ROR-1, Inhibits a protein selected from the group consisting of Syk, PKC, Hsp90, XPO1 and combinations thereof. In some embodiments, two additional therapeutic agents (eg, an inhibitor of mTOR and an inhibitor of BCL-2) are administered.

In some embodiments, the additional therapeutic agent is a protein selected from the group consisting of anti-apoptotic protein, heat shock protein, nuclear efflux protein, kinase, histone deacetylase, E3 ubiquitin ligase, histone-lysine N-methyltransferase, and combinations thereof. Suppress.

In some embodiments, the additional therapeutic agent is PI3K, JAK-2, IRAK1, IRAK4, BMX, TAK1, Src family, HDAC6, MDM2, BCL-2, EZH2, EHMT2, PIM, JAK3, mTOR, ROR-1, Syk, Inhibits a protein selected from the group consisting of PKC, Hsp90, XPO1 and combinations thereof.

In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical composition thereof, and an additional therapeutic agent are administered simultaneously as separate dosages.

In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical composition thereof and the additional therapeutic agent are administered sequentially in any order as separate dosages. do.

Also provided herein is a method of treating a subject having cancer, comprising:

(a) administering to the subject at least one dose of a first BTK inhibitor for a predetermined period of time;

(b) After (a), the cancer cells in the sample obtained from the subject have at least one BTK inhibitor resistance mutation that confers to the cancer cells or tumors increased resistance to treatment with the first BTK inhibitor of step (a). Determining whether to have; And

(c) if the subject has cancer cells with at least one BTK inhibitor resistance mutation conferring increased resistance to treatment with the first BTK inhibitor of step (a) to the cancer cells or tumors, the subject is given formula I Administering a spray-dried dispersion of a compound of or a pharmaceutical composition thereof as monotherapy or in combination with another anticancer agent; or

(d) if the subject has cancer cells that do not have a BTK inhibitor resistance mutation conferring increased resistance to treatment with the first BTK inhibitor of step (a) to the cancer cells or tumors, the subject is given step (a) Administering an additional dose of the first BTK inhibitor of.

In some embodiments, the anticancer agent in step (c) is a second BTK inhibitor, immunotherapy, or a combination thereof.

In some embodiments, the anticancer agent in step (c) is the first BTK inhibitor administered in step (a).

In some embodiments, the anticancer agent in step (c) is selected from one or more kinase-targeted therapeutic agents. In some embodiments, the kinase-targeting therapeutic agent targets a kinase from a kinase family selected from JAK, Src, IRAK, and combinations thereof.

In some embodiments, the anticancer agent in step (c) consists of an anti-apoptotic protein, heat shock protein, nuclear efflux protein, kinase, histone deacetylase, E3 ubiquitin ligase, histone-lysine N-methyltransferase, and combinations thereof. It is a protein inhibitor that inhibits a protein selected from the group.

In some embodiments, the anticancer agent in step (c) consists of an anti-apoptotic protein, heat shock protein, nuclear efflux protein, kinase, histone deacetylase, E3 ubiquitin ligase, histone-lysine N-methyltransferase, and combinations thereof. It is selected from one or more protein inhibitors that inhibit a protein selected from the group.

In some embodiments, the protein inhibitor is PI3K, JAK-2, IRAK1, IRAK4, BMX, TAK1, Src family, HDAC6, MDM2, BCL-2, EZH2, EHMT2, PIM, JAK3, mTOR, ROR-1, Syk, PKC , Hsp90, XPO1 and combinations thereof.

In some embodiments, the subject is administered an additional dose of the first BTK inhibitor of step (a), and the method further comprises (e) administering to the subject another anticancer agent.

In some embodiments, the anticancer agent of step (e) is a second BTK inhibitor, immunotherapy, or a combination thereof.

In some embodiments, the anticancer agent of step (e) is a compound of Formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof.

Also provided herein is a method of treating a subject having cancer, comprising:

(a) administering to the subject at least one dose of a first BTK inhibitor for a predetermined period of time;

(b) After (a), the cancer cells in the sample obtained from the subject have at least one BTK inhibitor resistance mutation that confers to the cancer cells or tumors increased resistance to treatment with the first BTK inhibitor of step (a). Determining whether to have; And

(c) if the subject has cancer cells with at least one BTK inhibitor resistance mutation conferring increased resistance to treatment with the first BTK inhibitor of step (a) to the cancer cell or tumor, the subject is given a second Administering a BTK inhibitor as monotherapy or in combination with another anticancer agent; or

(d) if the subject has cancer cells that do not have a BTK inhibitor resistance mutation conferring increased resistance to treatment with the first BTK inhibitor of step (a) to the cancer cells or tumors, the subject is given step (a) Administering an additional dose of the first BTK inhibitor, wherein the mutation is a substitution at amino acid position 481, for example C481S, C481F, C481T, C481G and C481R.

In some embodiments, the anticancer agent of step (c) is the first BTK inhibitor administered in step (a).

In some embodiments, the subject is administered an additional dose of the first BTK inhibitor of step (a), and the method further comprises (e) administering another anticancer agent.

In some embodiments, the anticancer agent of step (e) is a second BTK inhibitor, immunotherapy, or a combination thereof.

In some embodiments, the anticancer agent of step (e) is a pharmaceutical composition of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

Also provided herein is a method of treating a subject having cancer, comprising:

(a) administering to the subject at least one dose of a first BTK inhibitor for a predetermined period of time;

(b) After (a), the cancer cells in the sample obtained from the subject have at least one BTK inhibitor resistance mutation that confers to the cancer cells or tumors increased resistance to treatment with the first BTK inhibitor of step (a). Determining whether to have; And

(c) if the subject has cancer cells with at least one BTK inhibitor resistance mutation conferring increased resistance to treatment with the first BTK inhibitor of step (a) to the cancer cells or tumors, the subject is given formula I Administering a spray-dried dispersion or pharmaceutical composition according to a compound of or a pharmaceutically acceptable salt thereof as monotherapy or with another anticancer agent; or

(d) if the subject has cancer cells that do not have a BTK inhibitor resistance mutation conferring increased resistance to treatment with the first BTK inhibitor of step (a) to the cancer cells or tumors, the subject is given step (a) An additional dose of a first BTK inhibitor of, wherein the mutation is at one or more amino acid positions 244, 257, 334, 495, 664, 665, 707, 708, 742, 845, 848, 993, 1140 or 1141 of PLCγ2. A step that is a substitution in

Also provided herein is a method of treating a subject having cancer, comprising:

(a) Cancer cells in a sample obtained from a subject having cancer and previously administered one or more doses of a first BTK inhibitor exhibit increased resistance to treatment with a first BTK inhibitor previously administered to the subject. Determining whether it has at least one BTK inhibitor resistance mutation conferring to the cancer cell or tumor; And

(b) if the subject has cancer cells with at least one BTK inhibitor resistance mutation conferring to the cancer cells or tumors increased resistance to treatment with a first BTK inhibitor previously administered to the subject, the subject is given the formula Administering a spray-dried dispersion or pharmaceutical composition of a compound of I or a pharmaceutically acceptable salt thereof as monotherapy or with another anticancer agent; or

(c) if the subject has cancer cells that do not have a BTK inhibitor resistance mutation that confers increased resistance to treatment with a first BTK inhibitor previously administered to the subject to the cancer cells or tumors, the subject has a first BTK Administering an additional dose of an inhibitor.

Also provided herein is a method of treating a subject having cancer, comprising:

(a) Cancer cells in a sample obtained from a subject having cancer and previously administered one or more doses of a first BTK inhibitor exhibit increased resistance to treatment with a first BTK inhibitor previously administered to the subject. Determining whether it has at least one BTK inhibitor resistance mutation conferring to the cancer cell or tumor; And

(b) if the subject has cancer cells with at least one BTK inhibitor resistance mutation that confers to the cancer cells or tumors increased resistance to treatment with a first BTK inhibitor previously administered to the subject, 2 administering to the subject a BTK inhibitor as monotherapy or in combination with another anticancer agent; or

(c) if the subject has cancer cells or cancer cells that do not have a BTK inhibitor resistance mutation that confers increased resistance to treatment with a first BTK inhibitor previously administered to the subject, to the subject, previously administered to the subject. Administering an additional dose of the first BTK inhibitor.

Also provided herein is a method of treating a subject having cancer, comprising:

(a) administering at least one dose of a spray-dried dispersion or pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof for a predetermined period of time;

(b) After (a), the cancer cells in the sample obtained from the subject are increased resistance to treatment with a spray-dried dispersion or pharmaceutical composition of the compound of formula I of step (a) or a pharmaceutically acceptable salt thereof. Determining whether it has one or more BTK inhibitor resistance mutations that confer to the cancer cells or tumors; And

(c) increased treatment with the spray-dried dispersion according to any one of claims 1 to 3 of step (a) or the pharmaceutical composition according to any of claims 7 to 93 Administering a second BTK inhibitor as monotherapy or in combination with another anticancer agent to a subject having cancer cells with one or more BTK inhibitor resistance mutations that confer resistance to the cancer cells or tumors; or

(d) having a BTK inhibitor resistance mutation that confers to cancer cells or tumors increased resistance to treatment with a spray-dried dispersion or pharmaceutical composition of the compound of formula I of step (a) or a pharmaceutically acceptable salt thereof. Administering an additional dose of a spray-dried dispersion or pharmaceutical composition of a compound of formula I of step (a) or a pharmaceutically acceptable salt thereof to a subject having cancer cells that do not have cancer cells.

Also provided herein is a method of treating a subject having cancer, comprising:

(a) Cancer cells in a sample obtained from a subject having cancer and previously administered one or more doses of a spray-dried dispersion or pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof have been previously administered to the subject. Determining whether it has one or more BTK inhibitor resistance mutations that confer to cancer cells or tumors increased resistance to treatment with a spray-dried dispersion or pharmaceutical composition of an administered compound of formula I or a pharmaceutically acceptable salt thereof. The step of doing;

(b) at least one BTK inhibitor that confers to cancer cells or tumors increased resistance to treatment with a spray-dried dispersion or pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof previously administered to a subject. Administering a second BTK inhibitor as monotherapy or in combination with another anticancer agent to a subject having cancer cells bearing the resistant mutation; or

(c) a BTK inhibitor resistance mutation that confers to cancer cells or tumors increased resistance to treatment with a spray-dried dispersion or pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof previously administered to a subject. Administering an additional dose of a spray-dried dispersion or pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof previously administered to a subject having cancer cells that do not have cancer cells.

Also provided herein is a method of treating a BTK-associated cancer in a subject, comprising:

(a) administering to a subject identified or diagnosed as having BTK-associated cancer one or more doses of a spray-dried dispersion or pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof as monotherapy;

(b) after step (a), determining the level of circulating tumor DNA in the biological sample obtained from the subject; And

(c) a spray-dried dispersion or pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof to a subject identified as having approximately the same or an elevated level of circulating tumor DNA compared to a reference level of circulating tumor DNA, and Administering an additional therapeutic agent or treatment.

In some embodiments, the additional therapeutic agent is a second BTK kinase inhibitor. In some embodiments, the additional therapeutic agent or treatment comprises one or more of radiation therapy, chemotherapeutic agents, checkpoint inhibitors, surgery, and one or more second kinase inhibitors.

In some embodiments, the reference level of circulating tumor DNA is the level of circulating tumor DNA in a biological sample obtained from a subject prior to step (a).

(i) confirmed or diagnosed to have a BTK-associated cancer, and (ii) previously administered as monotherapy a spray-dried dispersion or pharmaceutical composition of one or more doses of a compound of formula I or a pharmaceutically acceptable salt thereof. And (ii) after administration of one or more doses of a spray-dried dispersion or pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof as monotherapy, approximately equal to the reference level of circulating tumor DNA or Administering to a subject identified as having elevated levels of circulating tumor DNA a therapeutically effective amount of a spray-dried dispersion or pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof and an additional therapeutic agent or treatment. , Methods of treating BTK-associated cancer in a subject are also provided herein.

In some embodiments, the reference level of circulating tumor DNA is one or more doses of a compound of Formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof as a monotherapy. The level of circulating tumor DNA in a biological sample obtained from a subject prior to administration.

In some embodiments, the additional therapeutic agent is a second BTK kinase inhibitor. In some embodiments, the additional therapeutic agent or treatment comprises one or more of radiation therapy, chemotherapeutic agents, checkpoint inhibitors, surgery, and one or more second protein inhibitors.

(i) confirmed or diagnosed to have a BTK-associated cancer, (ii) previously administered at least one dose of a second BTK kinase inhibitor, and (ii) after administration of at least one dose of a second BTK kinase inhibitor , A spray-dried dispersion or pharmaceutical of a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof for a subject identified as having an approximately equal or elevated level of circulating tumor DNA compared to a reference level of circulating tumor DNA. Also provided herein is a method of selecting a treatment for a subject comprising the step of selecting a composition.

(i) confirmed or diagnosed to have a BTK-associated cancer, and (ii) previously administered as monotherapy a spray-dried dispersion or pharmaceutical composition of one or more doses of a compound of formula I or a pharmaceutically acceptable salt thereof. And (ii) after administration of one or more doses of a spray-dried dispersion or pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof, a level of approximately equal or elevated compared to the reference level of circulating tumor DNA. A subject comprising the step of selecting a spray-dried dispersion or pharmaceutical composition of a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof for a subject identified as having circulating tumor DNA and an additional therapeutic treatment. Also provided herein is a method of selecting a treatment for.

In some embodiments, the reference level of circulating tumor DNA is one or more doses of a compound of Formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof as a monotherapy. The level of circulating tumor DNA in a biological sample obtained from a subject prior to administration. In some embodiments, the additional therapeutic treatment is a second BTK kinase inhibitor. In some embodiments, the additional therapeutic treatment includes one or more of radiation therapy, chemotherapeutic agents, checkpoint inhibitors, and one or more second protein inhibitors.

Also provided herein is a method of determining the efficacy of a treatment in a subject, comprising:

(a) determining a first level of circulating tumor DNA in a biological sample obtained from a subject identified or diagnosed with a BTK-associated cancer at a first time point;

(b) after the first time point and before the second time point, administering to the subject a treatment comprising one or more doses of a spray-dried dispersion or pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof;

(c) determining a second level of circulating tumor DNA in the biological sample obtained from the subject at a second time point; And

(d) confirming that the treatment is effective in a subject determined to have a reduced second level of circulating tumor DNA compared to the first level of circulating tumor DNA; Or confirming that the treatment is not effective in a subject determined to have a second level of circulating tumor DNA that is approximately the same or elevated compared to the first level of circulating tumor DNA.

Also provided herein is a method of determining whether a subject has developed resistance to treatment, comprising:

(a) determining a first level of circulating tumor DNA in a biological sample obtained from a subject identified or diagnosed with a BTK-associated cancer at a first time point;

(b) after the first time point and before the second time point, administering to the subject a treatment comprising one or more doses of a spray-dried dispersion or pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof;

(c) determining a second level of circulating tumor DNA in the biological sample obtained from the subject at a second time point; And

(d) determining that a subject with a reduced second level of circulating tumor DNA compared to the first level of circulating tumor DNA did not develop resistance to treatment; Or determining that a subject having a second level of circulating tumor DNA that is approximately the same or elevated compared to the first level of circulating tumor DNA has developed resistance to treatment.

In some of any of the above embodiments, the subject does not have active uncontrolled autoimmune cytopenia. In some embodiments, the subject has not been diagnosed with autoimmune cytopenia. In some embodiments, the subject does not have a history of clinically significant uncontrolled heart, cardiovascular disease, or myocardial infarction within 6 months of initiating treatment as described herein. In some embodiments, the subject has not been diagnosed with a heart or cardiovascular disease. In some embodiments, the subject did not have a myocardial infarction. In some embodiments, the subject does not have a clinically significant active malabsorption syndrome. In some embodiments, the subject has not been diagnosed with malabsorption syndrome. In some embodiments, the subject has a strong cytochrome P450 3A4 (CYP3A4) inhibitor (e.g., ritonavir, indinavir, nelpinavir, saquinavir, clarithromycin, telithromycin) during any treatment as described herein. Tromycin, chloramphenicol, ketoconazole, itraconazole, posaconazole, voriconazole, nefazodone and cobicistat) or an inducer (e.g. carbamazepine, dexamethasone, etosuccimide, glucocorticoid, griseofulvin, phenytoin) , Primidone, progesterone, rifampin, naphcillin, nlpinavir, nevirapine, oxcarbazepine, phenobarbital, phenylbutazone, rofecoxib (mild), St. John's wort, sulfadimidine, sulfinpyrazone and troglitazone) It is not being treated with. In some embodiments, the subject is treated with a proton pump inhibitor (e.g., omeprazole, lansoprazole, dexlansoprazole, esomeprazole, pantoprazole, rabeprazole, ilaprazole) within 7 days of initiating any treatment described herein. Not being cured. In some embodiments, the subject does not have an active second malignancy. In some embodiments, the subject has an active second malignancy in remission and the subject has an life expectancy of> 2 years.

Also herein is a method of inhibiting BTK kinase activity in a mammalian cell comprising contacting the mammalian cell with a spray-dried dispersion, pharmaceutical composition or polymorphic form of a compound of formula I or a pharmaceutically acceptable salt thereof. Is provided in.

Autoimmune or inflammatory in a subject comprising administering to the subject a spray-dried dispersion or pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof to a subject identified or diagnosed as having an autoimmune or inflammatory disease. Methods of treating diseases are also provided herein.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials for use in the present invention are described herein; Other suitable methods and materials known in the art may also be used. The materials, methods, and examples are illustrative only and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

The details of one or more embodiments of the invention are set forth in the accompanying drawings and the detailed description below. Other features, objects and advantages of the present invention will be apparent from the detailed description and drawings, and from the claims.

1 is an X-ray powder diffraction scan of Form A of a compound of formula I (free base).
2A-2B are scans of mixtures of Forms A and B of compounds of formula I. 2A is a differential scanning calorimetry (DSC) scan of a mixture of polymorph Form A and Form B of a compound of Formula I. ^{2B is a 1} H NMR spectrum of a mixture of polymorph Form A and Form B of the compound of formula (I).
3A-3B are scans of Form C of the compound of Formula I. ^{3A is a 1} H NMR spectrum of Form C of compound I. 3B is a differential scanning calorimetry scan of Form C of a compound of Formula I (hemi-1,4-dioxane solvate).
4A-4C are scans of Form A of a compound of Formula I. 4A is an X-ray powder diffraction scan of Form A of a compound of Formula I. ^{4B is a 1} H NMR spectrum of Form A of compound I. 4C is a differential scanning calorimetry scan of Form A of a compound of Formula I.
5 is an adjusted DSC scan of a spray-dried dispersion prototype of a compound of formula (I).
6 is an X-ray powder diffraction scan of a prototype spray-dried dispersion of a compound of formula (I).
7 is a thermogravimetric analysis (TGA) scan of a spray-dried dispersion prototype of a compound of formula I.
Figure 8 shows the dissolution of a tablet comprising a spray-dried dispersion of a compound of formula I and a HPMCAS polymer.
9 shows the concentration of compounds of formula I in plasma over time of in vivo dog bioavailability and pharmacokinetic studies.
10A-10D show the dose response effect on Y223 autophosphorylation in HEK293 cells stably expressing BTK and BTK C481S. 10A and 10B show the effect of the compound of formula I and ibrutinib dose response on Y223 autophosphorylation in HEK293 cells stably expressing BTK (tBTK; total BTK) (FIG. 10A) and BTK C481S (FIG. 10B ). It is a Western blot showing. 10C and 10D are dose response curves generated from Western blot data for Y223 autophosphorylation in HEK293 cells stably expressing BTK (FIG. 10C) and BTK C481S (FIG. 10D ). Compounds of formula I inhibited autophosphorylation of BTK Y223 in both wild-type and C481S mutant proteins with IC50 values of 8.6 ± 0.3 nM and 8.8 ± 1.8 nM, respectively. Ibrutinib inhibited BTK wild type with an IC50 of 5.7±0.5 nM, and its activity against the C481S mutant could not be fitted to the IC50 curve.
11A is a Western blot showing the dose response of a compound of Formula I to BTK Y223 and PLCγ2 Y1217 phosphorylation in Ramos RA1 cells. 11B and 11C are plots of Western blot data for BTK Y223 (FIG. 11B) and PLCγ2 Y1217 phosphorylation (FIG. 11C) in Ramos RA1 cells. The compound of formula I inhibited the autophosphorylation of BTK Y223 with an IC ₅₀ of 3.2 ± 0.6 nM, and the phosphorylation of PLCγ2 Y1217 with an IC ₅₀ of 8.2 nM ± 4.3.
12A is a plot showing the dose response inhibition of compounds of Formula I on TMD8 proliferation. FIG. 12B is a plot showing inhibitor concentration versus area under the curve (AUC) (mean±SD) from FIG. 12A. Quantification of the area under the curve (AUC) for each individual curve allowed the determination _{of the IC 50 2.33 nM of the compound of formula I for TMD8 proliferation.}
13A-C show dose-dependent inhibition of tumor growth in an OCI-Ly10 human B-cell lymphoma cell line xenograft tumor mouse model. 13A shows tumor growth with tumor volume expressed as mean±SEM for a human B-cell lymphoma cell line xenograft tumor mouse model administered with the indicated vehicle or inhibitor. 13B shows tumor growth after treatment is stopped in a human B-cell lymphoma cell line xenograft tumor mouse model. 13C shows normalized body weight values expressed as mean±SEM of mice during treatment.
14A-C show dose-dependent inhibition of tumor growth in a TMD8 human B-cell lymphoma cell line xenograft tumor mouse model. 14A shows tumor growth with tumor volume expressed as mean±SEM for a TMD8 human B-cell lymphoma cell line xenograft tumor mouse model administered with the indicated vehicle or inhibitor. 14B shows the tumor weight after 14 days of administration of the compound of formula I in a TMD8 human B-cell lymphoma cell line xenograft tumor mouse model. 14C shows normalized body weight values expressed as mean±SEM for mice during treatment.
15A-B show the concentration of compounds of formula I in plasma over 48 hours in dogs. 15A shows the concentration of the compound of formula I in plasma for fed or fasting dogs fed individuals administered a crystalline compound of formula I in suspension. FIG. 15B shows the concentration of the compound of formula I in plasma for individual fed or fasting dogs administered with the compound of formula I 50% SDI.
Similar reference symbols in the various drawings indicate similar elements.

Justice

As used herein, the term “polymorph” refers to crystals of the same compound with different physical properties as a result of the order of molecules in the crystal lattice. Different polymorphs of a single compound have one or more different chemical, physical, mechanical, electrical, thermodynamic and/or biological properties from each other. Differences in physical properties exhibited by polymorphs depend on pharmaceutical parameters such as storage stability, compressibility, density (important for composition and product preparation), dissolution rate (an important factor in determining bioavailability), solubility, melting point, chemical stability, physical stability. , Powder flowability, water sorption, compression and particle morphology can be affected. The difference in stability can be a change in chemical reactivity (e.g., a differential oxidation that causes a more rapid discoloration when a dosage form is composed of one polymorph compared to another polymorph) or a mechanical change (e.g. , Crystals change upon storage as the kinetically preferred polymorph is converted to a thermodynamically more stable polymorph) or both (e.g., one polymorph is more hygroscopic than the other). have. As a result of solubility/dissolution differences, some transitions affect potency and/or toxicity. Additionally, the physical properties of the crystal can be important in processing; For example, one polymorph may be more likely to form a solvate or may be difficult to filter and wash without impurities (i.e., the particle shape and size distribution may differ between one polymorph and the other. has exist). As used herein, "polymorph" does not include the amorphous form of the compound. As used herein, “amorphous” refers to an amorphous form of a compound, which may be a solid state form of the compound or a solubilized form of the compound. For example, "amorphous" refers to a compound (eg, a solid form of a compound) that does not have a molecule or an externally facing regularly repeating arrangement.

As used herein, the term "anhydrous" refers to a crystalline form of a compound of formula I having up to 1% by weight water, for example up to 0.5% by weight, up to 0.25% by weight or up to 0.1% by weight water.

As used herein, the term “solvate” refers to a crystalline form of a compound of formula I, such as a polymorphic form of the compound, wherein the crystal lattice comprises at least one crystallization solvent.

"Purity", when used in connection with a composition comprising a polymorph of a compound of formula I, refers to another polymorphic or amorphous form of one particular polymorphic form of a compound of formula I in the compositions mentioned. Refers to the percentage. For example, a composition comprising polymorph Form 1 having a purity of 90% will comprise 90 parts by weight of Form 1 and 10 parts by weight of other polymorph and/or amorphous forms of the compound of formula (I).

As used herein, a compound or composition is “substantially free of” such other ingredients when the compound or composition does not contain a significant amount of one or more other ingredients. For example, the composition may contain less than 5%, 4%, 3%, 2% or 1% by weight of other ingredients. Such components may include starting materials, residual solvents, or any other impurities that may result from the preparation and/or isolation of the compounds and compositions provided herein. In some embodiments, the polymorphic forms provided herein are substantially free of other polymorphic forms. In some embodiments, a particular polymorph of a compound of formula I is “substantially free of” other polymorphs when the particular polymorph makes up at least about 95% by weight of the compound of formula I in which it is present. In some embodiments, when a particular polymorph of a compound of formula I constitutes at least about 97%, about 98%, about 99%, or about 99.5% by weight of the compound of formula I in which the particular polymorph is present, "Substantially free from" other polymorphs. In certain embodiments, certain polymorphs of the compounds of formula I are “substantially free of” water when the amount of water constitutes up to about 2%, about 1%, or about 0.5% by weight of the polymorph.

As used herein, “substantially pure”, when used with respect to the polymorphic form of the compound of formula I, comprises 90%, 91%, 92%, 93%, 94%, 95 of the compound by weight of the compound. %, 96%, 97%, 98%, and 99% and also contain equal to about 100% of a polymorphic form of a compound having a purity greater than 90%. The remaining materials include other form(s) of the compound and/or reactive impurities and/or processing impurities resulting from their preparation. For example, the polymorphic form of the compound of formula I is substantially pure in that it has a polymorphic form of the compound of formula I of greater than 90% purity as determined by currently known and generally accepted means in the art. And the remaining less than 10% of the material comprises other form(s) and/or reactive impurities and/or processing impurities of the compound of formula (I). The presence of reactive impurities and/or processing impurities can be determined by analytical techniques known in the art, such as chromatography, nuclear magnetic resonance spectroscopy, mass spectrometry or infrared spectroscopy, and the like.

The term “about” preceding the values of DSC, TGA, TG, (glass transition temperature) or DTA (differential thermal analysis) reported in degrees Celsius has an acceptable variation of ±5°C.

To provide a more accurate description, some quantitative expressions herein are described as a range from about amount X to about amount Y. When a range is described, it is understood that the range is not limited to the stated upper and lower limits, but rather includes the entire range of about amount X to about amount Y, or any range therein.

“Room temperature” or “RT” refers to a typical laboratory ambient temperature, which is typically about 25°C.

“Spray-drying” refers to a method of preparing a dry powder from a solution or slurry. The solution or slurry is nebulized or dried rapidly with a hot gas such as air or nitrogen, allowing the solvent to evaporate rapidly and uniformly. "Spray-dried dispersion" refers to a powder obtained from a spray-drying process.

The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” refers to any and all solvents, co-solvents, complexing agents, dispersion media, coatings, antibacterial and antifungal agents, which are not biologically or otherwise undesirable, And isotonic agents and absorption delaying agents. The use of such media and agents for pharmaceutical active substances is well known in the art. Except where any conventional medium or agent is incompatible with the active ingredient, its use in the therapeutic compositions provided herein is contemplated. Supplementary active ingredients can also be incorporated into the composition. Additionally, various excipients may be included, such as those commonly used in the art. These and other such compounds are described, for example, in the Merck Index, Merck & Company, Rahway, NJ. Considerations for the inclusion of various ingredients in pharmaceutical compositions can be found in, for example, Gilman et al. (Eds.) (2010); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 12th Ed., The McGraw-Hill Companies.

As used herein, the terms “subject”, “individual” or “patient” are used interchangeably, and any animal such as a mammal such as a mouse, rat, other rodent, rabbit, dog, cat, pig, It refers to cattle, sheep, horses, primates and humans. In some embodiments, the subject is human.

In some embodiments, the subject has experienced and/or exhibited at least one symptom of a disease or disorder to be treated and/or prevented. In some embodiments, the subject has been identified or diagnosed as having a cancer (BTK-associated cancer) with dysregulation of the expression or activity or level of the BTK gene, BTK protein, or any of these (e.g., regulatory organs- Approved, e.g. when determined using an FDA-approved assay or kit). In some embodiments, the subject has a tumor that is positive for dysregulation of the expression or activity or level of the BTK gene, BTK protein, or any of them (e.g., as determined using a regulatory agency-approved assay or kit. ). The subject may be a subject having tumor(s) positive for dysregulation of the expression or activity or level of the BTK gene, BTK protein, or any of them (e.g., regulatory agency-approved, e.g., FDA- Confirmed positive using an approved assay or kit). The subject may be a subject whose tumor has a dysregulation of the BTK gene, BTK protein, or their expression or activity or level (e.g., wherein the tumor is a regulatory agency-approved, e.g., an FDA-approved kit. Or confirmed like this using a test). In some embodiments, the subject is suspected of having a BTK-associated cancer. In some embodiments, the subject has been identified or diagnosed as having hematologic cancer. In some embodiments, the subject has been identified or diagnosed as having a B-cell malignancy. In some embodiments, the subject has a clinical record indicating that the subject has a tumor with dysregulation of the expression or activity or level of the BTK gene, BTK protein, or any of them (and optionally the clinical record is Indicating that it should be treated with any of the compositions provided). In some embodiments, the subject is a pediatric patient.

The term “pediatric patient” as used herein refers to a patient under the age of 21 at the time of diagnosis or treatment. The term “child” refers to a newborn (from birth to the first month); Infants (from 1 month to 2 years old); Children (2 to 12 years old); And adolescents (ages 12 to 21 (until 22nd birthday, but not including)). Berhman RE, Kliegman R, Arvin AM, Nelson WE, Textbook of Pediatrics, 15th Ed. Philadelphia: W.B. Saunders Company, 1996; Rudolph AM, et al., Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; And Avery MD, First LR, Pediatric Medicine, 2nd Ed. Baltimore: Williams &Wilkins; 1994]. In some embodiments, the pediatric patient is from birth to the first 28 days of life, from 29 days to less than 2 years, from 2 to 12 years, or from 12 to 21 years (until but not including the 22nd birthday). )to be. In some embodiments, the pediatric patient is from birth to the first 28 days of life, 29 days to less than 1 year, 1 month to less than 4 months, 3 months to less than 7 months, 6 months to less than 1 year, 1 From 2 to under 2 years old, 2 to under 3 years old, 2 to 7 years old, 3 to 5 years old, 5 to 10 years old, 6 to 13 years old, 10 years old It is up to 15 years of age, or 15 to under 22 years of age.

As used herein, the term “treat” or “treatment” refers to a therapeutic or palliative measure. The beneficial or desired clinical outcome, whether detectable or undetectable, is a complete or partial alleviation of the symptoms associated with the disease or disorder or condition, a decrease in the severity of the disease, a stabilized (i.e., not exacerbating) condition of the disease, the disease progression. Delay or slowing of the disease, amelioration or alleviation of the disease state (eg, one or more symptoms of the disease), and remission (whether partial or total). “Treatment” can also mean prolonged survival compared to expected survival if not receiving treatment.

The term “therapy” refers to administering to a subject one or more doses of an active compound or pharmaceutical agent as part of a treatment regimen.

In one embodiment, the term “preventing” as used herein refers to a number of types of diseases or conditions as described herein (eg, inflammatory pain, neuropathic pain and pain associated with cancer, surgery and fractures). Pain) or the onset, reoccurrence, or spread of the whole or part of its symptoms.

The term “progression” refers to cancer that worsens or spreads within the body, as defined by the National Cancer Institute (NCI Dictionary of Cancer Terms). For example, progression may be an increase in the number of cancer cells in a subject, an increase in the size of one or more tumors in the subject, an increase in tumor burden, an increase in the rate or degree of metastasis, an overall or partial worsening of symptoms associated with cancer, or of a disease. Increasing the degree and/or accelerating disease progression. “Progress” can also mean shortened survival compared to expected survival if not receiving therapy. In some embodiments, the progression is one of an increase in the percentage of blast cells, an increase in the ratio of bone marrow to red blood cells, an increase in dysplasia (e.g., leukocyte dysplasia), an increase in the percentage of myeloid plasma cells, and an increase in the percentage of myeloid lymphocytes. It may include detecting abnormalities (eg, Sever, et al., Arch Pathol Lab Med. 2016 Sep;140(9):932-49) (which is incorporated herein by reference in its entirety). Reference). In some embodiments, progression can include detecting one or more of an increase in the percentage of leukocytes (eg, polymorphonuclear leukocytes), a decrease in platelet count, and a decrease in hemoglobin in the peripheral blood. In some embodiments, tumor burden can be assessed using RECIST (eg, RECIST version 1 or version 1.1). See, eg, Eisenhauer et al., Eur. J. Cancer. 2009, 45(2):228-47], which is incorporated herein by reference in its entirety. In some embodiments, tumor burden can be assessed using PERCIST. See, eg, Wahl, et al. J. nucl. med. 2009, 50:122S-150S], which is incorporated herein by reference in its entirety.

The term “recurrence” refers to the signs and symptoms of a disease or return of a disease after a period of improvement, as defined by the National Cancer Institute (NCI Dictionary of Cancer Terms). For example, recurrence may result in an increase in the number of cancer cells in the subject after a period of improvement, an increase in the size of one or more tumors in the subject, an increase in the tumor burden, an increase in the rate or degree of metastasis, a total or partial worsening of symptoms associated with cancer. , Detecting an increase in the severity of the disease and/or an acceleration of disease progression. In some embodiments, recurrence may include progression of the cancer after a period of improvement. In some embodiments, the period of improvement is a decrease in the number of cancer cells in the subject, a decrease in the size of one or more tumors in the subject, a decrease in the tumor burden, a decrease in the rate or degree of metastasis, a total or partial improvement in symptoms associated with cancer, And detecting a decrease in the severity of the disease and/or slowing the progression of the disease. In some embodiments, the recurrence is of an increase in the percentage of blast cells, an increase in the ratio of bone marrow to red blood cells, an increase in dysplasia (e.g., leukocyte dysplasia), an increase in the percentage of myeloid plasma cells, and an increase in the percentage of myeloid lymphocytes after the improvement period. It may include detecting one or more. In some embodiments, the period of improvement is one or more of a decrease in the percentage of blast cells, a decrease in the ratio of bone marrow to red blood cells, a decrease in dysplasia (e.g., leukocyte dysplasia), a decrease in the percentage of myeloid plasma cells, and a decrease in the percentage of bone marrow. It may include detecting. In some embodiments, the recurrence may include detecting one or more of an increase in the percentage of white blood cells (e.g., polymorphonuclear leukocytes), a decrease in platelet count, and a decrease in hemoglobin in the peripheral blood after the improvement period. In some embodiments, the period of improvement may include detecting one or more of a decrease in the percentage of leukocytes (eg, polymorphonuclear leukocytes), an increase in platelet count, and an increase in hemoglobin in the peripheral blood.

“Recurrence” may also include “recurrence”, which is typically defined by the National Cancer Institute as a cancer that recurs after a period in which the cancer cannot be detected. Cancer can return to the same location in the body as the original (primary) tumor or to another location in the body (NCI Dictionary of Cancer Terms). In some embodiments, not detecting cancer may include not detecting cancer cells in the subject, not detecting tumors in the subject, and/or wholly or partially absent from symptoms associated with cancer.

As used herein, the terms “tolerant” and “tolerant” refer to unplanned hospitalization during therapy, discontinuation of therapy and/or decrease in therapy dose, functional decrease due to therapy, and the occurrence of a severe, impaired or life-threatening adverse event. / Or may refer to leading to a decrease in performance status. In some embodiments, a decrease in performance status can be assessed using the Eastern Collaborative Oncology Group (ECOG) Performance Status Scale (see, eg, Oken et al. Am. J. Clin. Oncol. 5:649- 655 (1982)] (which is incorporated herein by reference in its entirety). In some embodiments, a decrease in performance status can be assessed using Karnowski performance status (eg, Peus et al., BMC Med. Inform. Decis. Mak. 13: 72 (2013)). (See, which is incorporated herein by reference in its entirety). In some embodiments, the subject is a pediatric patient, and the performance status is assessed by a Lansky performance score (eg, Lansky et al., Cancer. 60(7):1651-6 (1987)), which is The entirety of which is incorporated herein by reference).

As used herein, the term “preventing” refers to the prevention of the onset, reoccurrence or spread of a disease or condition as described herein, or wholly or partially of a symptom thereof.

The term “administering” or “administering” refers to a method of providing a dose of a compound or pharmaceutical composition to a vertebrate or invertebrate, including mammals, birds, fish or amphibians. The preferred method of administration may depend on a variety of factors, such as the components of the pharmaceutical composition, the site of the disease and the severity of the disease.

A “therapeutically effective amount” or “pharmaceutically effective amount” of a compound provided herein is an amount sufficient to achieve the desired effect and may vary depending on the nature and severity of the disease state and the potency of the compound. The therapeutic effect is alleviation to some degree of one or more of the symptoms of the disease, and may include cure of the disease. “Healing” means that the symptoms of the active disease are eliminated. However, certain long-term or permanent effects of the disease (eg, extensive tissue damage) may exist even after healing has been achieved.

The phrase “dysregulation of the expression or activity or level of a gene, protein, or any of them” refers to a gene mutation (eg, a chromosomal translocation that causes the expression of a fusion protein comprising a kinase domain and a fusion partner, compared to a wild-type protein. A mutation in a gene that causes the expression of a protein containing a deletion of at least one amino acid, a mutation in a gene that causes the expression of a protein having one or more point mutations compared to a wild-type protein, at least one insertion compared to a wild-type protein A mutation in a gene that causes the expression of a protein having a modified amino acid, a gene duplication that produces an increased level of protein in a cell, or a regulatory sequence that produces an increased level of protein in a cell (e.g., promoter and/or enhancer ), an alternative spliced version of an mRNA that produces a protein with deletion of at least one amino acid in the protein compared to a wild-type protein), or aberrant cell signaling and/or dysregulation autocrine/perisecretion Refers to increased expression (eg, increased levels) of wild-type protein in mammalian cells due to signaling (eg, compared to control non-cancerous cells). As another example, dysregulation of the expression or activity or level of a gene, protein, or any of them is a protein having increased activity or constitutively active compared to a protein encoded by a gene that does not contain the mutation. It may be a mutation in the encoding gene. For example, dysregulation of the expression or activity or level of a gene, protein, or any of them is a first portion of a protein comprising a functional kinase domain and a second portion of a partner protein (i.e., not the primary protein). It may be the result of a gene or chromosomal translocation that causes the expression of a fusion protein containing In some instances, dysregulation of the expression or activity or level of a gene, protein, or any of these may be the result of a gene translocation of one gene to a different gene.

The phrase “dysregulation of the expression or activity or level of a BTK gene, BTK kinase, or any of these” refers to increased expression of a BTK kinase, increased transcription of a BTK gene, or increased activation or phosphorylation of a BTK kinase. By way of example, the dysregulation of the expression or activity or level of the BTK gene, BTK protein, or any of these, is at least 1 compared to a gene mutation (e.g., a BTK gene translocation that causes the expression of a fusion protein, a wild-type BTK protein). A deletion in the BTK gene that causes the expression of the BTK protein, including a deletion of the amino acid of the dog, or a mutation in the BTK gene that causes the expression of the BTK protein with one or more point mutations), or overexpression of the BTK protein in the cell or BTK BTK gene amplification, which induces autocrine activity resulting from overexpression of the gene, causing an increase in the pathogenicity of the activity of the kinase domain of the BTK protein (e.g., a constitutively active kinase domain of the BTK protein) in the cell. have. As another example, the dysregulation of the expression or activity or level of the BTK gene, BTK protein, or any of these is compared to wild-type BTK mRNA, starting from an alternative promoter and alternatively a splice of BTK mRNA or BTK mRNA transcribed. It may be a printed version. In some embodiments, an alternatively spliced version of BTK mRNA produces BTK with a deletion of at least one amino acid in the BTK protein compared to a wild-type BTK protein. In some embodiments, BTK mRNA transcribed from an alternative promoter compared to wild-type BTK kinase produces a BTK kinase with at least one amino acid added to the N-terminus of the BTK kinase compared to wild-type BTK kinase. As another example, the dysregulation of the expression or activity or level of the BTK gene, the BTK protein, or any of them has an increased activity or constitutively active compared to the protein encoded by the BTK gene that does not contain the mutation. It may be a mutation in the BTK gene encoding the phosphorus BTK protein. Further examples of dysregulation of the expression or activity or level of the BTK gene, BTK protein, or any of these are BTK inhibitor resistance mutations. Non-limiting examples of BTK inhibitor resistance mutations are described in Table 2.

In some embodiments, the dysregulation of the expression or activity or level of a BTK gene, BTK kinase, or any of these is a dysregulation of the expression or activity or level of a BCR signaling pathway gene, a BCR signaling pathway protein, or any of these. to be. In some embodiments, the dysregulation of the expression or activity or level of a BCR signaling pathway gene, a BCR signaling pathway protein, or any of these, is one or more activating mutations in the BCR complex or downstream signaling component, present in the tissue microenvironment. It is a ligand-independent tonic BCR signaling that causes continuous BCR stimulation by microbial antigens or autoantigens, or pathogenic increase in the expression or activation of BTK protein. In some embodiments, the dysregulation of the expression or activity or level of a BCR signaling pathway gene, a BCR signaling pathway protein, or any of these is overexpression or over-activation of one or more BCR signaling pathway proteins. For example, dysregulation of the expression or activity or level of the BTK gene, BTK protein, or any of these may be the result of a gene mutation in the BCR signaling pathway protein (e.g., BCR causing the expression of a fusion protein. Signal transduction pathway gene translocation, a deletion in the BCR signaling pathway gene, or one or more point mutations resulting in the expression of the BCR signaling pathway protein comprising a deletion of at least one amino acid compared to the wild-type BCR signaling pathway protein. A mutation in the BCR signaling pathway gene that causes the expression of the BCR signaling pathway protein, or a BCR signaling pathway protein that causes the deletion of at least one amino acid in the BCR signaling pathway protein compared to a wild-type BCR signaling pathway protein is created. An alternative spliced version of the BCR signaling pathway protein mRNA). Non-limiting examples of BCR signaling pathway mutations are described in Table 4. Further examples of dysregulation of the expression or activity or level of the BTK gene, BTK protein, or any of these are BTK inhibitor resistance mutations. Non-limiting examples of BTK inhibitor resistance mutations in the BCR signaling pathway protein are described in Table 3.

The term “BTK-associated disease or disorder” as used herein refers to the expression of a BTK gene, a BTK kinase (also referred to herein as a BTK kinase protein or BTK kinase), or any of them (eg, one or more) or Any type of dysregulation of activity or level (e.g., any type of dysregulation of the expression or activity or level of a BTK gene, BTK kinase, BTK kinase domain, or any of these described herein) Refers to. Non-limiting examples of BTK-associated diseases or disorders include, for example, cancer and autoimmune disorders such as arthritis or lupus.

As used herein, the term “BTK-associated cancer” refers to a cancer associated with or having dysregulation of the expression or activity or level of a BTK gene, a BTK kinase (also referred to herein as a BTK kinase protein or BTK kinase), or any of these. Refers to. Non-limiting examples of BTK-associated cancers are described herein.

The term “activating mutation” describes a mutation in a gene that, when assayed, eg under the same conditions, results in the expression of a protein with increased activity, eg compared to a wild-type protein. For example, activating mutations can lead to expression of a fusion protein comprising a kinase domain and a fusion partner. In another example, the activating mutation is one or more (e.g., 2, 3, 4, 5, 6) with increased protein activity compared to, e.g., wild-type protein, e.g., when assayed under the same conditions. , 7, 8, 9 or 10) of amino acid substitutions (eg, any combination of any amino acid substitutions described herein). In another example, the activating mutation is one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9) compared to, e.g., a wild-type protein, e.g., when assayed under the same conditions. Or it may be a mutation in a gene that causes the expression of a protein in which 10) amino acids have been deleted. In another example, the activating mutation is at least one (e.g., at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 12, at least 14, at least 16, at least 18 or at least 20) amino acids may be mutations in the gene that cause the expression of the inserted protein.

In some embodiments, an “activating mutation” describes a mutation in a BTK kinase gene that causes the expression of a BTK kinase with increased kinase activity, eg, compared to a wild-type BTK kinase, when assayed under the same conditions. do. For example, activating mutations can lead to expression of a fusion protein comprising a BTK kinase domain and a fusion partner. In another example, the activating mutation is one or more with increased kinase activity (e.g., 2, 3, 4, 5, compared to, e.g., wild-type BTK kinase, e.g., when assayed under the same conditions. 6, 7, 8, 9 or 10) amino acid substitutions (eg, any combination of any amino acid substitutions described herein). In another example, the activating mutation is at least one (e.g., 2, 3, 4, 5, 6, 7, 8, 9 or 10) amino acids may be a mutation in the BTK kinase gene that causes the expression of the deleted BTK kinase. In another example, the activating mutation is at least one (e.g., at least 2, at least 3, compared to a wild-type BTK kinase, e.g., an exemplary wild-type BTK kinase described herein, e.g., when assayed under the same conditions. BTK, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 12, at least 14, at least 16, at least 18 or at least 20) amino acids that induce the expression of an inserted BTK kinase It may be a mutation in the kinase gene. Additional examples of activating mutations are known in the art.

In some embodiments, an “activating mutation” is a BCR signal that, when assayed, eg, under the same conditions, results in the expression of a BCR signaling pathway protein with increased activity compared to, eg, a wild type BCR signaling pathway protein. The mutations in the transduction pathway protein gene are described. For example, activating mutations can cause expression of a fusion protein comprising a BCR signaling pathway protein domain and a fusion partner. In another example, the activating mutation is one or more (e.g., 2, 3, 4, Mutations in the BCR signaling pathway protein gene that cause the expression of BTK kinase with 5, 6, 7, 8, 9 or 10 amino acid substitutions (e.g., any combination of any amino acid substitutions described herein) Can be In another example, the activating mutation is at least one (e.g., 2, 3, 4, 5, 6, 7) compared to, e.g., a wild-type BCR signaling pathway protein, e.g., when assayed under the same conditions. , 8, 9 or 10) amino acids may be a mutation in the BCR signaling pathway protein gene that causes the expression of the deleted BCR signaling pathway protein. In another example, the activating mutation is at least one (e.g., at least 2, at least 3, at least 4, at least 5, at least 6, compared to a wild-type BCR signaling pathway protein, e.g., when assayed under the same conditions, At least 7, at least 8, at least 9, at least 10, at least 12, at least 14, at least 16, at least 18 or at least 20) amino acids in the BCR signaling pathway protein gene that cause the expression of the inserted BCR signaling pathway protein It can be a mutation. Additional examples of activating mutations are known in the art.

The term “wild type” or “wild type” refers to not having a BTK-associated disease, for example a BTK-related cancer (optionally also without an increased risk of developing a BTK-related disease and/or not suspected of having a BTK-related disease. Is not found in a subject), or does not have a BTK-associated disease, e.g., a BTK-related cancer (optionally also does not have an increased risk of developing a BTK-related disease and/or is not suspected of having a BTK-related disease. ) Describe a nucleic acid (eg, BTK gene or BTK mRNA) or protein (eg, BTK protein) found in cells or tissues from a subject.

The term "regulatory agency" refers to a state agency for approval of medical use of pharmaceutical agents by the state. For example, a non-limiting example of a regulatory body is the United States Food and Drug Administration (FDA).

“BTK kinase inhibitor” as defined herein includes any compound that exhibits BTK inhibitory activity. In some embodiments, the BTK kinase inhibitor is selective for BTK kinase. Exemplary BTK kinase inhibitors are less than about 1000 nM, less than about 500 nM, less than about 200 nM, less than about 100 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM, as measured in an assay as described herein. Or less than about 1 nM of BTK kinase inhibitory activity (IC ₅₀ ). _{In some embodiments, the BTK kinase inhibitor has an inhibitory activity against BTK kinase (IC 50} ) of less than about 25 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM, as measured in an assay as provided herein. Can be indicated.

As used herein, a “first BTK kinase inhibitor” or “first BTK inhibitor” is a BTK kinase inhibitor as defined herein, but a compound of formula I or a pharmaceutically acceptable salt thereof, amorphous or It does not include polymorphic forms, spray-dried dispersions thereof, or pharmaceutical compositions thereof. As used herein, a “second BTK kinase inhibitor” or “second BTK inhibitor” is a BTK kinase inhibitor as defined herein, but a compound of formula I or a pharmaceutically acceptable salt thereof, amorphous or Does not include polymorphic forms. When both the first and second BTK inhibitors are present in the methods provided herein, the first and second BTK kinase inhibitors are different.

The term “immunotherapy” refers to an agent that modulates the immune system. In some embodiments, immunotherapy can increase the expression and/or activity of modulators of the immune system. In some embodiments, immunotherapy can reduce the expression and/or activity of modulators of the immune system. In some embodiments, immunotherapy can mobilize and/or enhance the activity of immune cells.

The term “pharmaceutical combination” as used herein refers to a pharmaceutical therapy resulting from a mixture or combination of more than one active ingredient and includes both fixed and non-fixed combinations of active ingredients.

The term “fixed combination” refers to a compound of formula (I) or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical composition thereof and at least one additional therapeutic agent (eg, chemical Therapies) are both administered to a subject simultaneously in a single composition or dosage form.

The term “non-fixed combination” refers to a compound of formula (I) or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical composition thereof and at least one additional therapeutic agent (e.g. , Chemotherapeutic agents) are formulated as separate compositions or dosage forms such that they can be administered simultaneously, concurrently or sequentially to a subject in need thereof, under variable intervention time limits, wherein such administration is at an effective level within the body of the subject. It means to provide two or more kinds of compounds. They also apply to cocktail therapy, for example the administration of three or more active ingredients.

The term “metastasis” is a term known in the art and refers to the formation of an additional tumor (eg, a solid tumor) in a subject or at a site away from the primary tumor in the subject, wherein the additional tumor is a primary tumor and It contains the same or similar cancer cells.

The phrase “risk of developing metastasis” refers to the risk that a subject or subject with a primary tumor will develop an additional tumor (eg, a solid tumor) at a site away from the primary tumor in the subject or subject over a defined period of time, Wherein the additional tumor comprises cancer cells identical or similar to the primary tumor. Described herein are methods of reducing the risk of developing metastasis in a subject or subject with cancer.

The phrase “risk of developing further metastasis” refers to a subject having a primary tumor and one or more additional tumors at a site away from the primary tumor, wherein the one or more additional tumors comprise cancer cells that are the same or similar to the primary tumor. Or the risk that the subject will develop one or more additional tumors away from the primary tumor, wherein the additional tumors contain cancer cells that are the same or similar to the primary tumor. Methods of reducing the risk of developing further metastasis are described herein.

As used herein, the term “contacting” refers to bringing together the indicated moieties in an in vitro system or in an in vivo system. For example, “contacting” a BTK kinase with a compound provided herein means administering a compound provided herein to an individual or subject having a BTK kinase, such as a human, as well as, for example, a cellular or And introducing a compound provided herein into a sample containing the purified formulation.

The phrase “effective amount” when administered to a subject in need of such treatment (i) treats a BTK kinase-associated disease or disorder, or (ii) attenuates, ameliorates, or ameliorates one or more symptoms of a particular disease, condition or disorder. Means an amount of a compound sufficient to eliminate, or (iii) delay the onset of one or more symptoms of a particular disease, condition or disorder described herein. The amount of a compound of formula (I) or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical composition thereof that will correspond to such an amount may be determined by the specific compound, disease state and severity thereof, in need of treatment. It will depend on factors such as the identity of the subject (eg, body weight), but can nevertheless be determined commercially by one of ordinary skill in the art.

1. Pharmaceutical composition of the compound of formula I

The present disclosure relates to a pharmaceutical composition comprising a polymer and a compound of formula (I) or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof:

More specifically, compounds of formula I useful for the treatment and prevention of diseases that can be treated with BTK kinase inhibitors, including BTK-associated diseases and disorders, and pharmaceutically acceptable salts thereof, spray-dried in amorphous or polymorphic form It relates to a dispersion or oral pharmaceutical composition.

Spray-dried dispersion

Spray-dried dispersions comprising a compound of formula I and a hypromellose acetate succinate (HPMCAS) polymer are provided herein. Non-limiting examples of HPMCAS polymers include HPMCAS-MG, HPMCAS-LF, HPMCAS-LG, HPMCAS-MF, HMPCAS-HF and HPMCAS-HG. HPMCAS type L is a polymer with a high succinoyl substitution to acetyl substitution ratio (S/A ratio), whereas type H HPMCAS is a polymer with a low S/A ratio, and type M HPMCAS polymer has an intermediate S/A ratio. . HPMCAS types F and G represent fine and granular particle sizes, respectively. In some embodiments, the ratio of the compound of Formula I to the HPMCAS polymer is from about 1:4 to about 4:1. In some embodiments, the ratio of the compound of Formula I to the HPMCAS polymer is about 4:1, about 3:1, about 7:3, about 13:7, about 3:2, about 11:9, about 1:1, It is about 9:11, about 2:3, about 7:13, about 3:7, about 1:3, or about 1:4. In some embodiments, the ratio of the compound of Formula I to the HPMCAS polymer is about 1:1. In some embodiments, the HPMCAS polymer is HPMCAS-LF, HPMCAS-LG, HPMCAS-MF, HMPCAS-HF, HPMCAS-HG, or a combination thereof. In some embodiments, the HPMCAS polymer is HPMCAS-MG.

Also provided herein is a method of preparing a spray-dried dispersion of a compound of formula (I). The method includes adding an HPMCAS polymer to a compound of formula (I) and spray-drying the mixture to form a spray-dried dispersion. In some embodiments, the ratio of the compound of Formula I to the HPMCAS polymer is from about 1:4 to about 4:1. In some embodiments, the ratio of the compound of Formula I to the HPMCAS polymer is about 4:1, about 3:1, about 7:3, about 13:7, about 3:2, about 11:9, about 1:1, It is about 9:11, about 2:3, about 7:13, about 3:7, about 1:3, or about 1:4. In some embodiments, the ratio of the compound of Formula I to the HPMCAS polymer is about 1:1. In some embodiments, the ratio of the compound of Formula I to the HPMCAS polymer is about 1:1. In some embodiments, the HPMCAS polymer is HPMCAS-MG.

In some embodiments, the compound of formula (I) is dissolved in one or more solvents to form a solution and then spray-dried. In some embodiments, the solvent is one or more organic solvents. In some embodiments, the organic solvent is selected from the group consisting of methanol, acetone, dichloromethane, tetrahydrofuran, and combinations thereof. In some embodiments, the solvent is a mixture of an organic solvent and water. In some embodiments, the solvent is a mixture of tetrahydrofuran and water. For example, the organic solvent can be 95:5 tetrahydrofuran:water. In some embodiments, the organic solvent is a mixture of dichloromethane and methanol. For example, the organic solvent may be 80:20 w/w% volume of dichloromethane:methanol. In another example the solvent is 100% methanol. In some embodiments, Compound Form A of Formula I is dissolved in one or more organic solvents.

In some embodiments, the solution of the compound of formula (I) is polish-filtered before the HPMCAS polymer is added. In some embodiments, a solution of the compound of Formula I and the HPMCAS polymer is polish-filtered and then spray-dried. In some embodiments, the HPMCAS polymer is HPMCAS-MG.

In some embodiments, the HPMCAS polymer is dissolved in an organic solvent. In some embodiments, the HPMCAS polymer is HPMCAS-MG.

In some embodiments, the HPMCAS polymer is dissolved in one or more solvents. In some embodiments, the solvent is one or more organic solvents. In some embodiments, the organic solvent is selected from the group consisting of methanol, acetone, dichloromethane, tetrahydrofuran, and combinations thereof. In some embodiments, the solvent is a mixture of an organic solvent and water. In some embodiments, the solvent is a mixture of tetrahydrofuran and water. For example, the organic solvent can be 95:5 tetrahydrofuran:water. In some embodiments, the organic solvent is a mixture of dichloromethane and methanol. For example, the organic solvent can be 80:20 w/w% dichloromethane:methanol. In another example the solvent is 100% methanol. Then the compound of formula I is added and dissolved. In some embodiments, the HPMCAS polymer is HPMCAS-MG.

The method further comprises the step of spray-drying a solution of the compound of formula I and the HPMCAS polymer. In some embodiments, the HPMCAS polymer is HPMCAS-MG.

In some embodiments, the method further comprises drying the spray-dried dispersion. In some embodiments, the spray-dried dispersion is dried, for example to remove residual solvent. In some embodiments, the spray-dried dispersion is dried in an oven. In some embodiments, the spray-dried dispersion is dried at a temperature of about 30°C to about 50°C. In some embodiments, the spray-dried dispersion is dried at a temperature of about 35°C to about 45°C, such as about 40°C. In some embodiments, the spray-dried dispersion is dried under vacuum under an _{N 2 purge.} In some embodiments, the spray-dried dispersion is about 10 to about 40 hours, about 30 to about 60 hours, about 50 to about 80, about 70 to about 100 hours, about 40 hours, about 50 hours, about 60 hours. , Dried for a period of about 70 hours, about 80 hours, about 90 hours or about 100 hours. In some embodiments, the spray dried dispersion contains less than about 40,000 ppm of solvent, less than about 20,000 ppm of solvent, less than about 10,000 ppm of solvent, or less than about 5,000 ppm of solvent, or , Dried until less than about 2,500 ppm of solvent remains, less than about 1,000 ppm of solvent remains, or less than about 600 ppm of solvent remains. In some embodiments, the solvent is a mixture of dichloromethane and methanol, and the spray-dried dispersion has less than about 2,000 ppm dichloromethane and less than about 15,000 ppm methanol remaining, or less than about 1,500 ppm dichloromethane and about 10,000. It is dried until less than ppm methanol remains, or less than about 600 ppm dichloromethane and less than about 3,000 ppm methanol remain. In some embodiments using 100% methanol as the solvent, the spray dried dispersion is dried until less than about 3,000 ppm methanol remains.

Pharmaceutical composition

Pharmaceutical compositions comprising a spray-dried dispersion of a compound of formula (I) and a HPMCAS polymer are also provided herein. In some embodiments, the HPMCAS polymer is HPMCAS-MG.

In some embodiments, the pharmaceutical composition comprises a spray-dried dispersion and a first composition having one or more pharmaceutical excipients, wherein the spray-dried dispersion comprises an HPMCAS polymer and a compound of formula I as described herein. Includes. In some embodiments, the HPMCAS polymer is HPMCAS-MG.

In some embodiments, the spray-dried dispersion is present in an amount of about 20% to about 75% w/w of the first composition. In some embodiments, the spray-dried dispersion comprises about 20% to about 50% w/w, about 50% to about 75% w/w, or about 30% to about 60% w/w of the first composition, For example, about 20% to about 40% w/w, about 30% to about 50% w/w, about 40% to about 60% w/w, or about 50 to about 75% w/w of the first composition. Exists in the amount of. In some embodiments, the spray-dried dispersion is about 30% to about 40% w/w, about 40% to about 50% w/w, about 50% to about 60% w/w of the composition, for example Present in an amount of about 35% w/w, about 40% w/w, about 45% w/w, about 50% w/w, about 55% w/w, or about 60% w/w of the first composition do.

In some embodiments, the pharmaceutical excipient of the first composition is selected from the group consisting of fillers, lubricants, and combinations thereof.

In some embodiments, the first composition described herein can include a filler. Fillers may include binders, diluents, disintegrants, lubricants and surfactants added to the pharmaceutical composition. In some embodiments, the fillers are saccharides (e.g., sugar, starch and cellulose), gelatin and synthetic polymers (e.g., polyvinylpyrrolidone, polyethylene glycol and poloxamers (e.g., polyoxyethylene and Poloxamer 188), which is a copolymer of polyoxypropylene. Exemplary fillers are glucose, sucrose, lactose (e.g. Foremost Fast Flo 316 lactose monohydrate), starch (modified starch, such as sodium starch glycolate (e.g., Explotop ( EXPLOTAB)®)], xylitol, dextrin, saccharose, sorbitol, mannitol [for example, PARTECK® M 200 (mannitol with an average particle size of about 50 μm to about 500 μm) or Parr Tek® M 100 (mannitol with an average particle size less than 212 μm)] or Mannozem EZ spray dried mannitol, cellulose, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, polymethacrylate, dibasic calcium phosphate , Magnesium stearate, calcium stearate, sodium stearate, stearic acid, hydrogenated vegetable oil, mineral oil, sodium lauryl sulfate, magnesium lauryl sulfate, glyceryl palmitostearate, sodium benzoate, sodium stearyl fumarate , Colloidal silicon dioxide (e.g., sodium benzoate, sodium oleate, sodium acetate, alginic acid, alginate (e.g., Syloid 244FP), sodium alginate, calcium silicate, and ion exchange resins. Exemplary cellulose fillers are microcrystalline cellulose (eg, AVICEL® PH-101 (microcrystalline cellulose with an average particle size of approximately 50 μm) or Avicel® PH200 (with an average particle size of approximately 180 μm). Microcrystalline cellulose)] or Avicel® PH 102 methyl cellulose, ethyl cellulose, croscarmellose sodium (eg AC-Di Sol®), hydroxypropyl cellulose, and hydroxypropylmethylcellulose Exemplary polyvinylpyrrolidone fillers include crosslinked polyvinylpyrrolidone, such as KOLLIDON® CL (crospovidone with an average particle size of 90 μm to 130 μm) or Kollidon® CL-SF (With an average particle size of 10 μm to 30 μm Crospovidone). It is also contemplated that other fillers known to those skilled in the art are useful when formulated in the compositions described herein.

In some embodiments, the filler is glucose, sucrose, lactose, starch [including modified starch, such as sodium starch glycolate (Xplotap®)], xylitol, dextrin, saccharose, sorbitol, mannitol [e.g. For example, Partec® M 200 (mannitol with an average particle size of about 50 μm to about 500 μm) or Partec® M 100 (mannitol with an average particle size of less than 212 μm)], cellulose, polyvinylpyrrolidone , Polyethylene glycol, polyvinyl alcohol, polymethacrylate, dibasic calcium phosphate, magnesium stearate, calcium stearate, sodium stearate, stearic acid, hydrogenated vegetable oil, mineral oil, sodium lauryl sulfate, magnesium lauryl alcohol Pate, glyceryl palmitostearate, sodium benzoate, sodium stearyl fumarate, colloidal silicon dioxide, sodium benzoate, sodium oleate, sodium acetate, alginic acid, alginate (e.g. sodium alginate), calcium silicate, ion exchange Resin, or a combination thereof. In some embodiments, the cellulose is microcrystalline cellulose (e.g., Avicel® PH-101 (microcrystalline cellulose having an average particle size of approximately 50 μm) or Avicel® PH 200 (microcrystalline cellulose having an average particle size of approximately 180 μm). Crystalline cellulose)], methyl cellulose, ethyl cellulose, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropylmethylcellulose, or a combination thereof. In some embodiments, the polyvinylpyrrolidone is a crosslinked polyvinylpyrrolidone, such as Collidone® CL (crospovidone with an average particle size of 90 μm to 130 μm), Collidone® CL-SF (10 μm to 30 μm). crospovidone with an average particle size of μm) or a combination thereof.

In some embodiments, the filler is about 25% to about 80% w/w of the first composition, e.g., about 25% to about 50% w/w, about 50% to about 80% w/w of the first composition. , From about 40% to about 70% w/w. In some embodiments, the filler is about 30% to about 50% w/w, about 45% to about 65% w/w, about 55% to about 75% w/w of the first composition, e.g., the first composition Of about 40% w/w, about 45% w/w, about 50% w/w, about 55% w/w, about 60% w/w, about 65% w/w, or about 70% w/w Exists in the amount of.

In some embodiments, the filler is selected from binders, disintegrants, or combinations thereof.

Binders include agents that hold the active pharmaceutical ingredient and the inactive ingredient together in a cohesive mixture. Exemplary binders are glucose, sucrose, lactose, starch [including modified starches such as sodium starch glycolate (Xplotap®)], xylitol, dextrin, saccharose, sorbitol, mannitol [eg, Parr Tek® M 200 (mannitol with an average particle size of about 50 μm to about 500 μm), Partec® M 100 (mannitol with an average particle size of less than 212 μm)], cellulose, polyvinylpyrrolidone, polyethylene glycol , Polyvinyl alcohol, polymethacrylate and sodium starch glycolate. Exemplary cellulose fillers are microcrystalline cellulose (e.g., Avicel® PH-101 (microcrystalline cellulose with an average particle size of approximately 50 μm) or Avicel® PH 200 (microcrystalline cellulose with an average particle size of approximately 180 μm). )], methyl cellulose, ethyl cellulose, croscarmellose sodium, hydroxypropyl cellulose and hydroxypropylmethylcellulose. Exemplary polyvinylpyrrolidone fillers are crosslinked polyvinylpyrrolidone, such as Collidone® CL (crospovidone with an average particle size of 90 μm to 130 μm) or Collidone® CL-SF (10 μm to 30 μm). Crospovidone having an average particle size). It is also contemplated that other binders known to those skilled in the art are useful when formulated in the compositions described herein.

In some embodiments, the binder is about 30% to about 80% w/w of the first composition, e.g., about 30% to about 50% w/w, about 50% to about 80% w/w of the first composition. , From about 40% to about 70% w/w. In some embodiments, the filler is about 30% to about 50% w/w, about 35% to about 55% w/w, about 40% to about 60% w/w, about 45% to about 65 of the first composition. % w/w, about 55% to about 75% w/w, for example about 40% w/w, about 45% w/w, about 50% w/w, about 52% w/w of the first composition , About 55% w/w, about 60% w/w, about 65% w/w, or about 70% w/w.

In some embodiments, the binder is microcrystalline cellulose, cellulose ether, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxy methyl cellulose starch, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, mannitol, xylitol, sorbitol , Lactose, sucrose, sorbitol, gelatin, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, polymethacrylate, and combinations thereof.

In some embodiments, the binder is microcrystalline cellulose, mannitol, or a combination thereof. In some embodiments, the microcrystalline cellulose is from about 5% to about 80% w/w of the first composition, e.g., from about 5% to about 40% w/w, from about 40% to about 80% w of the first composition. /w, about 20% to about 60% w/w, about 5% to about 30% w/w, about 30% to about 55% w/w, about 10% to about 40% w/w, or about 15 % To about 35% w/w. In some embodiments, the microcrystalline cellulose is from about 10% to about 20% w/w, from about 20% to about 30% w/w, from about 30% to about 40% w/w, from about 40% to about 40% of the first composition. About 50% w/w, about 50% to about 60% w/w, or about 60% to about 70% w/w, for example about 15% w/w, about 20% w/w of the first composition , About 25% w/w, about 26% w/w, about 30% w/w, about 35% w/w, about 40% w/w, about 45% w/w, about 50% w/w, Or about 60% w/w.

In some embodiments, mannitol is from about 5% to about 80% w/w of the first composition, e.g., from about 5% to about 40% w/w, from about 40% to about 80% w/w of the first composition. , About 20% to about 60% w/w, about 5% to about 30% w/w, about 30% to about 55% w/w, about 10% to about 40% w/w, or about 15% to It is present in an amount of about 35% w/w. In some embodiments, mannitol is about 10% to about 20% w/w, about 20% to about 30% w/w, about 30% to about 40% w/w, about 40% to about 50 of the first composition. % w/w, about 50% to about 60% w/w, or about 60% to about 70% w/w, for example about 15% w/w, about 20% w/w of the first composition, about 25% w/w, about 26% w/w, about 30% w/w, about 35% w/w, about 40% w/w, about 45% w/w, about 50% w/w, or about It is present in an amount of 60% w/w.

In some embodiments, the binder is a combination of microcrystalline cellulose and mannitol. In some embodiments, the microcrystalline cellulose is from about 5% to about 40% w/w, from about 40% to about 75% w/w, from about 20% to about 60% w/w, from about 5% to about 5% of the first composition. About 30% w/w, about 30% to about 55% w/w, about 10% to about 40% w/w, or about 15% to about 35% w/w, wherein mannitol is the first From about 5% to about 40% w/w, from about 40% to about 75% w/w, from about 20% to about 60% w/w, from about 5% to about 30% w/w, from about 30% of the composition About 55% w/w, about 10% to about 40% w/w, or about 15% to about 35% w/w. In some embodiments, the microcrystalline cellulose is from about 10% to about 20% w/w, from about 20% to about 30% w/w, from about 30% to about 40% w/w, from about 40% to about 40% of the first composition. About 50% w/w, about 50% to about 60% w/w, or about 60% to about 70% w/w, and mannitol is about 10% to about 20% w/w of the first composition. w, about 20% to about 30% w/w, about 30% to about 40% w/w, about 40% to about 50% w/w, about 50% to about 60% w/w, or about 60% To about 70% w/w. For example, microcrystalline cellulose is about 15% w/w, about 20% w/w, about 25% w/w, about 26% w/w, about 30% w/w, about 35% of the first composition. w/w, about 40% w/w, about 45% w/w, about 50% w/w, or about 60% w/w, and mannitol is about 15% w/w of the first composition , About 20% w/w, about 25% w/w, about 26% w/w, about 30% w/w, about 35% w/w, about 40% w/w, about 45% w/w, About 50% w/w, or about 60% w/w.

Disintegrants include any agent that promotes the destruction of the formulation in an aqueous environment, such as promoting a more rapid release of the active pharmaceutical ingredient. Exemplary disintegrants include, but are not limited to, starch and modified starches such as sodium starch glycolate, croscarmellose sodium, alginic acid, alginates such as sodium alginate, polyvinylpyrrolidone, calcium silicate and ion exchange resins. Does not. In one embodiment, the disintegrant is selected from sodium starch glycolate and croscarmellose sodium. Other disintegrants known to those skilled in the art are also contemplated to be useful when formulated in the compositions described herein.

In some embodiments, the disintegrant is from about 0.5% to about 5% w/w of the first composition, e.g., from about 0.5% to about 2.5% w/w, from about 2.5% w/w to about 5 of the first composition. % w/w, or about 1.5% to about 3.5% w/w. In some embodiments, the disintegrant is from about 0.5% to about 2% w/w, from about 1% to about 3% w/w, from about 2% to about 4% w/w, or from about 3% of the first composition. About 5% w/w, for example about 1% w/w, about 1.5% w/w, about 2% w/w, about 2.5% w/w, about 3% w/w, of the first composition 3.5% w/w, or about 4% w/w.

In some embodiments, the disintegrant is selected from the group consisting of sodium starch glycolate, alginic acid, sodium alginate, croscarmellose sodium, ion exchange resins, and combinations thereof. In one embodiment, the disintegrant is selected from sodium starch glycolate and croscarmellose sodium.

In some embodiments, sodium starch glycolate is about 0.5% to about 5% w/w of the first composition, for example about 0.5% to about 2.5% w/w, about 2.5% w/w of the first composition. To about 5% w/w, or about 1.5% to about 3.5% w/w. In some embodiments, sodium starch glycolate is about 0.5% to about 2% w/w, about 1% to about 3% w/w, about 2% to about 4% w/w, or about 3% to about 5% w/w, for example about 1% w/w, about 1.5% w/w, about 2% w/w, about 2.5% w/w, about 3% w/ of the first composition w, about 3.5% w/w, or about 4% w/w.

In some embodiments, the first composition described herein can include a lubricant. Lubricants are agents added to pharmaceutical formulations to reduce friction during processing. Exemplary lubricants include magnesium stearate, calcium stearate, sodium stearate, stearic acid, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulfate, glyceryl palmitostearate, sodium benzoate. , Sodium stearyl fumarate, colloidal silicon dioxide, sodium benzoate, sodium oleate and sodium acetate. Other lubricants known to those skilled in the art are also contemplated to be useful when formulated in the compositions described herein.

In some embodiments, the lubricant is from about 0.05% to about 2.5% w/w of the first composition, e.g., from about 0.05% w/w to about 1.25% w/w, from about 1.25% to about 2.5% of the first composition. w/w, or about 0.1% to about 1% w/w. In some embodiments, the lubricant is about 0.05% to about 0.15% w/w, about 0.15% to about 0.25% w/w, about 0.25% to about 0.35% w/w, about 0.35% to about 0.45 of the first composition. % w/w, from about 0.45% to about 0.55% w/w. In some embodiments, the lubricant is present in an amount of about 0.2% to about 0.3% w/w of the first composition. In some embodiments, the lubricant is about 0.1%, about 0.15%, about 0.2% w/w, about 0.25% w/w, about 0.3% w/w, about 0.35% w/w, about 0.4% of the first composition. w/w, about 0.45% w/w, about 1% w/w, about 1.5% w/w, or about 2% w/w.

In some embodiments, the lubricant is magnesium stearate and/or silicon dioxide. In some embodiments, the magnesium stearate is from about 0.05% to about 2.5% w/w of the first composition, e.g., from about 0.05% w/w to about 1.25% w/w, from about 1.25% to about the first composition. 2.5% w/w, or about 0.1% to about 1% w/w. In some embodiments, the magnesium stearate is from about 0.05% to about 0.15% w/w, from about 0.15% to about 0.25% w/w, from about 0.25% to about 0.35% w/w, from about 0.35% to about 0.35% of the first composition. About 0.45% w/w, about 0.45% to about 0.55% w/w. In some embodiments, the magnesium stearate is present in an amount of about 0.2% to about 0.3% w/w of the first composition. In some embodiments, the magnesium stearate is about 0.1%, about 0.15%, about 0.2% w/w, about 0.25% w/w, about 0.3% w/w, about 0.35% w/w, of the first composition. 0.4% w/w, about 0.45% w/w, about 1% w/w, about 1.5% w/w, or about 2% w/w.

In some embodiments, the spray-dried dispersion and pharmaceutical excipient are blended to form the first composition. In some embodiments, the first composition is granulated. In some embodiments, the first composition is granulated by roller compaction.

Pharmaceutical composition comprising the first composition

Pharmaceutical compositions comprising a first composition as described herein and one or more additional pharmaceutical excipients are also provided herein. In some embodiments, the first composition is present in an amount of about 15% to about 99% w/w of the total composition.

In some embodiments, the additional pharmaceutical excipient is selected from the group consisting of fillers, lubricants, lubricants, and combinations thereof.

In some embodiments, the lubricant is from about 0.05% to about 2% w/w of the total composition, e.g., from about 0.05% to about 1% w/w, from about 1% to about 2% w/w of the total composition, or From about 0.5% to about 1.5% w/w. In some embodiments, the lubricant is from about 0.05% to about 0.5% w/w, from about 0.1% to about 0.8% w/w, or from about 0.5% to about 1% w/w, e.g., of the total composition. About 0.1% w/w, about 0.2% w/w, about 0.3% w/w, about 0.4% w/w, or about 0.5% w/w.

In some embodiments, the lubricant is magnesium stearate, calcium stearate, sodium stearate, stearic acid, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulfate, glyceryl palmitostearate. , Sodium benzoate, sodium stearyl fumarate, colloidal silicon dioxide, sodium benzoate, sodium oleate, sodium acetate, and combinations thereof.

In some embodiments, the lubricant is magnesium stearate and/or silicon dioxide. In some embodiments, the magnesium stearate is from about 0.05% to about 2% w/w of the total composition, e.g., from about 0.05% to about 1% w/w, from about 1% to about 2% w/w of the total composition. , Or about 0.5% to about 1.5% w/w. In some embodiments, the magnesium stearate is from about 0.05% to about 0.5% w/w, from about 0.1% to about 0.8% w/w, or from about 0.5% to about 1% w/w, e.g., total composition. About 0.1% w/w, about 0.2% w/w, about 0.3% w/w, about 0.4% w/w, or about 0.5% w/w of the composition.

In some embodiments, the filler is present in an amount of about 1% to about 85% w/w of the total composition. In some embodiments, the filler is glucose, sucrose, lactose, starch [including modified starch, such as sodium starch glycolate (Xplotap®)], xylitol, dextrin, saccharose, sorbitol, mannitol [e.g. For example, Partec® M 200 (mannitol with an average particle size of about 50 μm to about 500 μm) or Partec® M 100 (mannitol with an average particle size of less than 212 μm)], cellulose, polyvinylpyrrolidone , Polyethylene glycol, polyvinyl alcohol, polymethacrylate, dibasic calcium phosphate, magnesium stearate, calcium stearate, sodium stearate, stearic acid, hydrogenated vegetable oil, mineral oil, sodium lauryl sulfate, magnesium lauryl alcohol Pate, glyceryl palmitostearate, sodium benzoate, sodium stearyl fumarate, colloidal silicon dioxide, sodium benzoate, sodium oleate, sodium acetate, alginic acid, alginate (e.g. sodium alginate), calcium silicate, ion exchange It is selected from the group consisting of resins, and combinations thereof. In some embodiments, the cellulose is microcrystalline cellulose (e.g., Avicel® PH-101 (microcrystalline cellulose having an average particle size of approximately 50 μm) or Avicel® PH 200 (microcrystalline cellulose having an average particle size of approximately 180 μm). Crystalline cellulose)], methyl cellulose, ethyl cellulose, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropylmethylcellulose, or a combination thereof. In some embodiments, the polyvinylpyrrolidone is a crosslinked polyvinylpyrrolidone, such as Collidone® CL (crospovidone with an average particle size of 90 μm to 130 μm) or Collidone® CL-SF (10 μm to 30 μm). crospovidone with an average particle size of μm). In some embodiments, the filler is a binder, a disintegrant, or a combination thereof.

In some embodiments, the filler comprises a disintegrant. In some embodiments, the disintegrant is about 0.5% to about 5% w/w of the total composition, e.g., about 0.5% to about 2.5% w/w, about 2.5% to about 5% w/w of the total composition, Or from about 1% to about 4% w/w. In some embodiments, the disintegrant is about 1% to about 2% w/w, about 1.5% to about 2.5% w/w, about 2% to about 3% w/w, about 2.5% to about 3.5 of the total composition. % w/w, or about 3% to about 4% w/w, for example about 1.5% w/w, about 2% w/w, about 2.5% w/w, about 3% w/w of the total composition , Or about 3.5% w/w.

In some embodiments, the disintegrant is selected from the group consisting of sodium starch glycolate, alginic acid, sodium alginate, ion exchange resins, and combinations thereof.

In some embodiments, the disintegrant is sodium starch glycolate or croscarmellose sodium. In some embodiments, sodium starch glycolate is from about 0.5% to about 5% w/w of the total composition, e.g., from about 0.5% to about 2.5% w/w, from about 2.5% to about 5% w of the total composition. /w, or about 1% to about 4% w/w. In some embodiments, sodium starch glycolate is about 1% to about 2% w/w, about 1.5% to about 2.5% w/w, about 2% to about 3% w/w, about 2.5% of the total composition. To about 3.5% w/w, or about 3% to about 4% w/w, e.g., about 1.5% w/w, about 2% w/w, about 2.5% w/w, about 3% of the total composition w/w, or about 3.5% w/w.

In some embodiments the composition includes a lubricant that is magnesium stearate. The lubricant is present at about 0.1% to about 1% wt/wt of the total composition by weight. In another embodiment, the lubricant is present in an amount of about 0.25% to 0.75% wt/wt, more preferably about 0.5% wt/wt of the total composition.

In some embodiments, the first composition is present in an amount of about 90% to about 99% w/w of the total composition. In some embodiments, the pharmaceutical composition comprises a first composition, a disintegrant and a lubricant. In some embodiments, the first composition is present in an amount of about 90% to about 99% w/w of the total composition, and the disintegrant is present in an amount of about 0.5% to about 5% w/w of the total composition, The lubricant is present in an amount of about 0.05% to about 2% w/w of the total composition. In some embodiments, the first composition is present in an amount of about 97% w/w of the total composition, the disintegrant is present in an amount of about 2.5% w/w of the total composition, and the lubricant is about 0.25% of the total composition. It is present in an amount of w/w.

In some embodiments, the disintegrant is sodium starch glycolate and the lubricant is magnesium stearate. In some embodiments, sodium starch glycolate is present in an amount of about 0.5% to about 5% w/w of the total composition, and magnesium stearate is present in an amount of about 0.05% to about 2% w/w of the total composition. exist. For example, sodium starch glycolate is present in an amount of about 0.5% to about 2.5% w/w, about 2.5% to about 5% w/w, or about 1% to about 4% w/w of the total composition. And magnesium stearate is present in an amount of about 0.05% to about 1% w/w, about 1% to about 2% w/w, or about 0.5% to about 1.5% w/w of the total composition. In some embodiments, sodium starch glycolate is about 1% to about 2% w/w, about 1.5% to about 2.5% w/w, about 2% to about 3% w/w, about 2.5% of the total composition. To about 3.5% w/w, or about 3% to about 4% w/w, wherein the magnesium stearate is from about 0.05% to about 0.5% w/w, from about 0.1% to about 0.8% of the total composition. w/w, or from about 0.5% to about 1% w/w. For example, sodium starch glycolate is in an amount of about 1.5% w/w, about 2% w/w, about 2.5% w/w, about 3% w/w, or about 3.5% w/w of the total composition. And magnesium stearate is present in an amount of about 0.1% w/w, about 0.2% w/w, about 0.3% w/w, about 0.4% w/w, or about 0.5% w/w of the total composition. do.

In other embodiments, the first composition is from about 15% to about 60% w/w of the total composition, e.g., from about 15% to about 35% w/w, from about 35% to about 60% w/w of the total composition. , Or from about 25% to about 45% w/w. In some embodiments, the first composition is from about 20% to about 30% w/w, from about 25% to about 35% w/w, from about 30% to about 40% w/w, from about 35% to about the total composition. 45% w/w, or about 40% to about 50% w/w, for example about 20% w/w, about 25% w/w, about 30% w/w, about 35% w/ of the total composition w, about 40% w/w, about 45% w/w, or about 50% w/w.

In some embodiments, the binder is about 40% to about 85% w/w of the total composition, e.g., about 40% w/w to about 60% w/w, about 60% to about 85% w/w of the total composition. w, or about 55% to about 75% w/w. In some embodiments, the binder is about 40% to about 50% w/w, about 45% to about 55% w/w, about 50% to about 60% w/w, about 55% to about 65% of the total composition. w/w, about 60% to about 70% w/w, about 65% to about 75% w/w, or about 70% to about 80% w/w. In some embodiments, the binder is about 45% w/w, about 50% w/w, about 55% w/w, about 60% w/w, about 62% w/w, about 65% w/w of the total composition. w, about 70% w/w, about 75% w/w, or about 80% w/w.

In some embodiments, the binder is microcrystalline cellulose, cellulose ether, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxy methyl cellulose starch, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, mannitol, xylitol, sorbitol , Lactose, sucrose, sorbitol, gelatin, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, polymethacrylate, and combinations thereof.

In some embodiments, the binder is microcrystalline cellulose, mannitol, or a combination thereof. In some embodiments, microcrystalline cellulose is from about 10% to about 85% w/w of the total composition, e.g., from about 10% to about 45% w/w, from about 45% to about 85%, or about It is present in an amount of 20% to about 60% w/w. In some embodiments, the microcrystalline cellulose is about 10% to about 20%, about 15% to about 25%, about 20% to about 30%, about 25% to about 35% w/w, about 30% of the total composition. To about 40% w/w, about 35% to about 45% w/w, or about 40% to about 50% w/w, for example about 20% w/w, about 25% w/w of the total composition , About 30% w/w, about 31% w/w, about 35% w/w, about 40% w/w, or about 45% w/w.

In some embodiments, mannitol is from about 10% to about 85% w/w of the total composition, e.g., from about 10% to about 45% w/w, from about 45% to about 85%, or about 20% of the total composition. To about 60% w/w. In some embodiments, mannitol is from about 10% to about 20%, from about 15% to about 25%, from about 20% to about 30%, from about 25% to about 35% w/w, from about 30% to about the total composition. 40% w/w, about 35% to about 45% w/w, or about 40% to about 50% w/w, for example about 20% w/w, about 25% w/w of the total composition, about 30% w/w, about 31% w/w, about 35% w/w, about 40% w/w, or about 45% w/w.

In some embodiments, microcrystalline cellulose and mannitol are present in an amount of about 10% to about 85% w/w of the total composition. For example, microcrystalline cellulose is present in an amount of about 10% to about 45% w/w, about 45% to about 85%, or about 20% to about 60% w/w of the total composition, and mannitol is From about 10% to about 45% w/w, from about 45% to about 85%, or from about 20% to about 60% w/w of the composition. In some embodiments, the microcrystalline cellulose is about 10% to about 20%, about 15% to about 25%, about 20% to about 30%, about 25% to about 35% w/w, about 30% of the total composition. To about 40% w/w, about 35% to about 45% w/w, or about 40% to about 50% w/w, and mannitol is from about 10% to about 20% of the total composition, about 15% to about 25%, about 20% to about 30%, about 25% to about 35% w/w, about 30% to about 40% w/w, about 35% to about 45% w/w, or about It is present in an amount of 40% to about 50% w/w. For example, microcrystalline cellulose is about 20% w/w, about 25% w/w, about 30% w/w, about 31% w/w, about 35% w/w, about 40% w of the total composition. /w, or about 45% w/w, and mannitol is about 20% w/w, about 25% w/w, about 30% w/w, about 31% w/w, about 35% w/w, about 40% w/w, or about 45% w/w.

In some embodiments, the first composition is blended with one or more pharmaceutical excipients. In some embodiments, the pharmaceutical composition is co-milled.

In some embodiments, pharmaceutical compositions as described herein are formulated as tablets. In some embodiments, the compound of formula (I) is from about 10 mg to about 50 mg, e.g., from about 10 mg to about 30 mg, from about 30 mg to about 50 mg, or from about 15 mg to about It is present in an amount of 35 mg. In some embodiments, the compound of Formula I is about 10 mg to about 20 mg, about 15 mg to about 25 mg, about 30 mg to about 40 mg, about 35 mg to about 45 mg, or In an amount of about 40 mg to about 50 mg, for example about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg exist.

In some embodiments, the compound of Formula I is from about 25 mg to about 220 mg, for example about 25 mg to about 120 mg, about 120 mg to about 220 mg, or about 70 mg to about, in a pharmaceutical composition formulated as a tablet. It is present in an amount of 170 mg. In some embodiments, the compound of Formula I is about 25 mg to about 75 mg, about 50 mg to about 100 mg, about 75 mg to about 125 mg, about 100 mg to about 150 mg, about 125 mg to about 175 mg, about 150 mg to about 200 mg, or about 175 mg to about 220 mg. In some embodiments, the compound of Formula I is about 50 mg to about 60 mg, about 60 mg to about 70 mg, about 70 mg to about 80 mg, about 80 mg to about 90 mg, about 85 mg to about 95 mg, About 90 mg to about 100 mg, 80 mg to about 120 mg, about 95 mg to about 105 mg, about 100 mg to about 110 mg, about 105 mg to about 115 mg, about 120 mg to about 130 mg, about 130 mg To about 140 mg, about 140 mg to about 150 mg, about 150 mg to about 160 mg, about 160 mg to about 170 mg, or about 170 mg to about 180 mg, for example about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg , About 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 170 mg, about 175 mg, or about 180 mg .

In some embodiments, the tablet is coated.

Also provided herein are pharmaceutical compositions comprising a compound of Formula I, an HPMCAS polymer and one or more pharmaceutical excipients. In some embodiments, the HPMCAS polymer is HPMCAS-MG.

In some embodiments, the one or more pharmaceutical excipients are selected from the group consisting of fillers, lubricants, and combinations thereof.

In some embodiments, the filler is glucose, sucrose, lactose, starch [including modified starch, such as sodium starch glycolate (Xplotap®)], xylitol, dextrin, saccharose, sorbitol, mannitol [e.g. For example, Partec® M 200 (mannitol with an average particle size of about 50 μm to about 500 μm) or Partec® M 100 (mannitol with an average particle size of less than 212 μm)], cellulose, polyvinylpyrrolidone , Polyethylene glycol, polyvinyl alcohol, polymethacrylate, dibasic calcium phosphate, magnesium stearate, calcium stearate, sodium stearate, stearic acid, hydrogenated vegetable oil, mineral oil, sodium lauryl sulfate, magnesium lauryl alcohol Pate, glyceryl palmitostearate, sodium benzoate, sodium stearyl fumarate, colloidal silicon dioxide, sodium benzoate, sodium oleate, sodium acetate, alginic acid, alginate (e.g. sodium alginate), calcium silicate, ion exchange Resin, or a combination thereof. In some embodiments, the cellulose is microcrystalline cellulose (e.g., Avicel® PH-101 (microcrystalline cellulose having an average particle size of approximately 50 μm) or Avicel® PH 200 (microcrystalline cellulose having an average particle size of approximately 180 μm). Crystalline cellulose)], methyl cellulose, ethyl cellulose, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropylmethylcellulose, or a combination thereof. In some embodiments, the polyvinylpyrrolidone is a crosslinked polyvinylpyrrolidone, such as Collidone® CL (crospovidone with an average particle size of 90 μm to 130 μm) or Collidone® CL-SF (10 μm to 30 μm). crospovidone with an average particle size of μm).

In some embodiments, the filler is selected from binders, disintegrants, or combinations thereof. In some embodiments, the binder is microcrystalline cellulose, cellulose ether, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxy methyl cellulose starch, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, mannitol, xylitol, sorbitol , Lactose, sucrose, sorbitol, gelatin, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, polymethacrylate, and combinations thereof. In some embodiments, the disintegrant is selected from the group consisting of sodium starch glycolate, alginic acid, sodium alginate, ion exchange resins, and combinations thereof.

In some embodiments, the lubricant is magnesium stearate, calcium stearate, sodium stearate, stearic acid, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulfate, glyceryl palmitostearate. , Sodium benzoate, sodium stearyl fumarate, colloidal silicon dioxide, sodium benzoate, sodium oleate, sodium acetate, and combinations thereof.

In some embodiments, the pharmaceutical composition comprises a compound of Formula I, an HPMCAS polymer, a binder, a disintegrant and a lubricant.

In some embodiments, the pharmaceutical composition is a compound of formula I present in an amount of about 5% to about 30% w/w of the total composition, HPMCAS present in an amount of about 5% to about 30% w/w of the total composition. Polymer, binder present in an amount of about 10% to about 90% w/w of the total composition, disintegrant present in an amount of about 0.5% to about 5% w/w of the total composition, and about 0.05% of the total composition To about 2% w/w. In some embodiments, the compound of formula I is present in an amount of about 5% to about 15% w/w of the total composition, and the HPMCAS polymer is present in an amount of about 5% to about 15% w/w of the total composition, and , The binder is present in an amount of about 70% to about 85% w/w of the total composition, the disintegrant is present in an amount of about 2.5% to about 4.5% w/w of the total composition, and the lubricant is It is present in an amount of 0.1% to about 1% w/w. For example, the compound of formula I is present in an amount of about 8% w/w of the total composition, the HPMCAS polymer is present in an amount of about 8% w/w of the total composition, and the binder is about 80% of the total composition. w/w, the disintegrant is present in an amount of about 3.5% w/w of the total composition, and the lubricant is present in an amount of about 0.3% w/w of the total composition. In some embodiments, the HPMCAS polymer is HPMCAS-MG.

In some embodiments, the binder is a combination of mannitol and microcrystalline cellulose. In some embodiments, the compound of formula I is present in an amount of about 5% to about 30% w/w of the total composition, and the HPMCAS polymer is present in an amount of about 5% to about 30% w/w of the total composition, and , Mannitol and microcrystalline cellulose are present in an amount of about 10% to about 90% w/w of the total composition, the disintegrant is present in an amount of about 0.5% to about 5% w/w of the total composition, and the lubricant It is present in an amount of about 0.05% to about 2% w/w of the total composition. In some embodiments, the compound of formula I is present in an amount of about 5% to about 15% w/w of the total composition, and the HPMCAS polymer is present in an amount of about 5% to about 15% w/w of the total composition, and , Microcrystalline cellulose and mannitol are present in an amount of about 70% to about 85% w/w of the total composition, the disintegrant is present in an amount of about 2.5% to about 4.5% w/w of the total composition, and the lubricant It is present in an amount of about 0.1% to about 1% w/w of the total composition. For example, the compound of formula I is present in an amount of about 8% w/w of the total composition, the HPMCAS polymer is present in an amount of about 8% w/w of the total composition, and mannitol and microcrystalline cellulose are present in the total composition. Is present in an amount of about 80% w/w, the disintegrant is present in an amount of about 3.5% w/w of the total composition, and the lubricant is present in an amount of about 0.3% w/w of the total composition. In some embodiments, mannitol and microcrystalline cellulose are present in a ratio of about 4:1, about 3:2, about 1:1, about 2:3, or about 1:4. In some embodiments, the HPMCAS polymer is HPMCAS-MG.

In some embodiments, the disintegrant is sodium starch glycolate. In some embodiments, the compound of formula I is present in an amount of about 5% to about 30% w/w of the total composition, and the HPMCAS polymer is present in an amount of about 5% to about 30% w/w of the total composition, and , The binder is present in an amount of about 10% to about 90% w/w of the total composition, sodium starch glycolate is present in an amount of about 0.5% to about 5% w/w of the total composition, and the lubricant is From about 0.05% to about 2% w/w of the composition. In some embodiments, the compound of formula I is present in an amount of about 5% to about 15% w/w of the total composition, and the HPMCAS polymer is present in an amount of about 5% to about 15% w/w of the total composition, and , The binder is present in an amount of about 70% to about 85% w/w of the total composition, sodium starch glycolate is present in an amount of about 2.5% to about 4.5% w/w of the total composition, and the lubricant is From about 0.1% to about 1% w/w of the composition. For example, the compound of formula I is present in an amount of about 8% w/w of the total composition, the HPMCAS polymer is present in an amount of about 8% w/w of the total composition, and the binder is about 80% of the total composition. w/w, sodium starch glycolate is present in an amount of about 3.5% w/w of the total composition, and lubricant is present in an amount of about 0.3% w/w of the total composition. In some embodiments, the HPMCAS polymer is HPMCAS-MG.

In some embodiments, the lubricant is magnesium stearate. In some embodiments, the compound of formula I is present in an amount of about 5% to about 30% w/w of the total composition, and the HPMCAS polymer is present in an amount of about 5% to about 30% w/w of the total composition, and , The binder is present in an amount of about 10% to about 90% w/w of the total composition, the disintegrant is present in an amount of about 0.5% to about 5% w/w of the total composition, and magnesium stearate is present in the total composition. Is present in an amount of about 0.05% to about 2% w/w. In some embodiments, the compound of formula I is present in an amount of about 5% to about 15% w/w of the total composition, and the HPMCAS polymer is present in an amount of about 5% to about 15% w/w of the total composition, and , The binder is present in an amount of about 70% to about 85% w/w of the total composition, the disintegrant is present in an amount of about 2.5% to about 4.5% w/w of the total composition, and magnesium stearate is present in the total composition. From about 0.1% to about 1% w/w of. For example, the compound of formula I is present in an amount of about 8% w/w of the total composition, the HPMCAS polymer is present in an amount of about 8% w/w of the total composition, and the binder is about 80% of the total composition. w/w, disintegrant is present in an amount of about 3.5% w/w of the total composition, and magnesium stearate is present in an amount of about 0.3% w/w of the total composition. In some embodiments, the HPMCAS polymer is HPMCAS-MG.

In some embodiments, the binder is a combination of microcrystalline cellulose and mannitol, the disintegrant is sodium starch glycolate, and the lubricant is magnesium stearate. In some embodiments, the pharmaceutical composition is a compound of formula I present in an amount of about 5% to about 30% w/w of the total composition, HPMCAS present in an amount of about 5% to about 30% w/w of the total composition. Polymer, microcrystalline cellulose present in an amount of about 30% to about 60% w/w of the total composition, mannitol present in an amount of about 30% to about 60% w/w of the total composition, about 0.5% of the total composition Sodium starch glycolate present in an amount from about 5% w/w, and magnesium stearate present in an amount from about 0.05% to about 2% w/w of the total composition. For example, the compound of formula I is present in an amount of about 8% w/w of the total composition, the HPMCAS polymer is present in an amount of about 8% w/w of the total composition, and microcrystalline cellulose is present in an amount of about 8% w/w of the total composition. Is present in an amount of 40% w/w, mannitol is present in an amount of about 40% w/w of the total composition, sodium starch glycolate is present in an amount of about 3.5% w/w of the total composition, and stear Magnesium acid is present in an amount of about 0.3% w/w of the total composition. In some embodiments, the HPMCAS polymer is HPMCAS-MG.

In another embodiment, the pharmaceutical composition is a compound of formula I present in an amount of about 10% to about 30% w/w of the total composition, HPMCAS present in an amount of about 10% to about 30% w/w of the total composition. Polymer, binder present in an amount of about 35% to about 70% w/w of the total composition, disintegrant present in an amount of about 2% to about 8% w/w of the total composition, and about 0.05% of the total composition To about 2% w/w. In some embodiments, the compound of formula I is present in an amount of about 15% to about 25% w/w of the total composition, and the HPMCAS polymer is present in an amount of about 15% to about 25% w/w of the total composition, and , The binder is present in an amount of about 40% to about 60% w/w of the total composition, the disintegrant is present in an amount of about 4% to about 6% w/w of the total composition, and the lubricant is It is present in an amount of 0.1% to about 1% w/w. For example, the compound of formula I is present in an amount of about 22% w/w of the total composition, the HPMCAS polymer is present in an amount of about 22% w/w of the total composition, and the binder is about 50% of the total composition. w/w, the disintegrant is present in an amount of about 5% w/w of the total composition, and the lubricant is present in an amount of about 0.5% w/w of the total composition. In some embodiments, the HPMCAS polymer is HPMCAS-MG.

In some embodiments, the binder is a combination of mannitol and microcrystalline cellulose. In some embodiments, the compound of formula I is present in an amount of about 10% to about 30% w/w of the total composition, and the HPMCAS polymer is present in an amount of about 10% to about 30% w/w of the total composition, and , Mannitol and microcrystalline cellulose are present in an amount of about 35% to about 70% w/w of the total composition, the disintegrant is present in an amount of about 2% to about 8% w/w of the total composition, and the lubricant It is present in an amount of about 0.05% to about 2% w/w of the total composition. In some embodiments, the pharmaceutical composition is a compound of formula I present in an amount of about 15% to about 25% w/w of the total composition, HPMCAS present in an amount of about 15% to about 25% w/w of the total composition. Polymer, mannitol and microcrystalline cellulose present in an amount of about 40% to about 60% w/w of the total composition, disintegrant present in an amount of about 4% to about 6% w/w of the total composition, and the total composition A lubricant present in an amount of about 0.1% to about 1% w/w of. For example, the compound of formula I is present in an amount of about 22% w/w of the total composition, the HPMCAS polymer is present in an amount of about 22% w/w of the total composition, and microcrystalline cellulose and mannitol are present in the total composition. Is present in an amount of about 50% w/w of, the disintegrant is present in an amount of about 5% w/w of the total composition, and the lubricant is present in an amount of about 0.5% w/w of the total composition. In some embodiments, mannitol and microcrystalline cellulose are present in a ratio of about 4:1, about 3:2, about 1:1, about 2:3, or about 1:4. In some embodiments, the HPMCAS polymer is HPMCAS-MG.

In some embodiments, the disintegrant is sodium starch glycolate. In some embodiments, the compound of formula I is present in an amount of about 10% to about 30% w/w of the total composition, and the HPMCAS polymer is present in an amount of about 10% to about 30% w/w of the total composition, and , The binder is present in an amount of about 35% to about 70% w/w of the total composition, sodium starch glycolate is present in an amount of about 2% to about 8% w/w of the total composition, and the lubricant is From about 0.05% to about 2% w/w of the composition. In some embodiments, the compound of formula I is present in an amount of about 15% to about 25% w/w of the total composition, and the HPMCAS polymer is present in an amount of about 15% to about 25% w/w of the total composition, and , The binder is present in an amount of about 40% to about 60% w/w of the total composition, sodium starch glycolate is present in an amount of about 4% to about 6% w/w of the total composition, and the lubricant is From about 0.1% to about 1% w/w of the composition. For example, the compound of formula I is present in an amount of about 22% w/w of the total composition, the HPMCAS polymer is present in an amount of about 22% w/w of the total composition, and the binder is about 50% of the total composition. w/w, sodium starch glycolate is present in an amount of about 5% w/w of the total composition, and lubricant is present in an amount of about 0.5% w/w of the total composition. In some embodiments, the HPMCAS polymer is HPMCAS-MG.

In some embodiments, the lubricant is magnesium stearate. In some embodiments, the compound of formula I is present in an amount of about 10% to about 30% w/w of the total composition, and the HPMCAS polymer is present in an amount of about 10% to about 30% w/w of the total composition, and , The binder is present in an amount of about 35% to about 70% w/w of the total composition, the disintegrant is present in an amount of about 2% to about 8% w/w of the total composition, and magnesium stearate is present in the total composition. Is present in an amount of about 0.05% to about 2% w/w. In some embodiments, the compound of formula I is present in an amount of about 15% to about 25% w/w of the total composition, and the HPMCAS polymer is present in an amount of about 15% to about 25% w/w of the total composition, and , The binder is present in an amount of about 40% to about 60% w/w of the total composition, the disintegrant is present in an amount of about 4% to about 6% w/w of the total composition, and magnesium stearate is present in the total composition. From about 0.1% to about 1% w/w of. For example, the compound of formula I is present in an amount of about 22% w/w of the total composition, the HPMCAS polymer is present in an amount of about 22% w/w of the total composition, and the binder is about 50% of the total composition. w/w, disintegrant is present in an amount of about 5% w/w of the total composition, and magnesium stearate is present in an amount of about 0.5% w/w of the total composition. In some embodiments, the HPMCAS polymer is HPMCAS-MG.

In some embodiments, the pharmaceutical composition is a compound of formula I present in an amount of about 10% to about 30% w/w of the total composition, HPMCAS present in an amount of about 10% to about 30% w/w of the total composition. Polymer, microcrystalline cellulose present in an amount of about 20% to about 30% w/w of the total composition, mannitol present in an amount of about 20% to about 30% w/w of the total composition, about 2% of the total composition Sodium starch glycolate present in an amount from about 8% w/w, and magnesium stearate present in an amount from about 0.05% to about 2% w/w of the total composition. In some embodiments, the HPMCAS polymer is HPMCAS-MG.

In some embodiments, the pharmaceutical composition comprises a compound of formula I present in an amount of about 22% w/w of the total composition, HPMCAS polymer present in an amount of about 22% w/w of the total composition, about 25% of the total composition. microcrystalline cellulose present in an amount of w/w, mannitol present in an amount of about 25% w/w of the total composition, sodium starch glycolate present in an amount of about 5% w/w of the total composition, and total Magnesium stearate present in an amount of about 0.5% w/w of the composition. In some embodiments, the HPMCAS polymer is HPMCAS-MG.

In some embodiments, pharmaceutical compositions as described herein are formulated as tablets. In some embodiments, the tablet is coated.

Also provided herein is a method of making a pharmaceutical composition as described herein, comprising:

Mixing the compound of formula (I), the HPMCAS polymer, and a solvent to form a solution;

Spray-drying the solution to form a spray-dried dispersion; And

Granulating the spray-dried dispersion to form a first composition.

In some embodiments, the HPMCAS polymer is HPMCAS-MG.

In some embodiments, the solvent is an organic solvent. In some embodiments, the organic solvent is selected from the group consisting of methanol, acetone, dichloromethane, tetrahydrofuran, and combinations thereof. In some embodiments, the solvent is a mixture of an organic solvent and water. In some embodiments, the solvent is a mixture of tetrahydrofuran and water. In some embodiments, the mixture is 95:5 tetrahydrofuran:water. In some embodiments, the organic solvent is a mixture of dichloromethane and methanol. In some embodiments, the organic solvent is 80:20 dichloromethane:methanol.

In some embodiments, the spray-dried dispersion is granulated after blending with one or more pharmaceutical excipients. In some embodiments, the spray-dried dispersion is granulated after drying in an oven. In some embodiments, the spray-dried dispersion is granulated after blending with one or more pharmaceutical excipients. In some embodiments, the spray-dried dispersion is granulated by roller compaction.

In some embodiments, the first composition is blended with one or more pharmaceutical excipients. In some embodiments, the first composition is co-milled. In some embodiments, the first composition is pressed into tablets. In some embodiments, the tablet is coated. In some embodiments, the coating includes a polymer, plasticizer, pigment, or combinations thereof.

In some embodiments, the ratio of the compound of Formula I to the HPMCAS polymer in the spray-dried dispersion is from about 1:4 to about 4:1. In some embodiments, the ratio of the compound of Formula I to the HPMCAS polymer is about 4:1, about 3:1, about 7:3, about 13:7, about 3:2, about 11:9, about 1:1, It is about 9:11, about 2:3, about 7:13, about 3:7, about 1:3, or about 1:4. In some embodiments, the ratio of the compound of Formula I to the HPMCAS polymer in the spray-dried dispersion is about 1:1. In some embodiments, the ratio of the compound of Formula I to the HPMCAS polymer in the spray-dried dispersion is about 1:1. In some embodiments, the HPMCAS polymer is HPMCAS-MG.

The daily dosage of a compound of formula I as described herein, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical composition thereof, is 1.0 to 10,000 mg per adult human per day. Or over a broader range or any range therein. For oral administration, the composition is preferably 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 20.0, 25.0, 30.0, 40.0, 50.0 for symptomatic adjustment of the dosage for the subject to be treated. Contains 60.0, 70.0, 75.0, 80.0, 90.0, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475 and 500 milligrams of active ingredient It is provided in the form of a tablet. An effective amount of the drug is typically supplied at a dosage level of about 0.1 mg/kg to about 1000 mg/kg body weight or any range therein per day. The range can be from about 0.5 to about 500 mg/kg body weight per day or any range therein. The range can be from about 1.0 to about 250 mg/kg body weight per day or any range therein. The range can be from about 0.1 to about 100 mg/kg body weight per day or any range therein. In one example, the range can be from about 0.1 to about 50.0 mg/kg body weight per day or any amount or range therein. In another example, the range can be from about 0.1 to about 15.0 mg/kg body weight per day or any range therein. In another example, the range can range from about 0.5 to about 7.5 mg/kg body weight per day or any amount therein. Pharmaceutical compositions as provided herein may be administered in a regimen of 1 to 4 times a day or as a single daily dose.

The optimal dosage to be administered can be readily determined by a person skilled in the art, and will vary depending on the mode of administration, the strength of the formulation, the mode of administration and the progression of the disease state. Additionally, factors associated with the particular subject to be treated, including subject age, weight, diet and time of administration, will cause the need to adjust the dosage.

Those skilled in the art will recognize that both in vivo and in vitro tests using suitable known generally acceptable cell and/or animal models predict the ability of a test compound to treat or prevent a given disorder. will be.

One of ordinary skill in the art would know that human clinical trials including first-human dose scoping and efficacy testing in healthy subjects and/or subjects suffering from a given disorder may be completed according to methods well known in the clinical and medical arts. You will further recognize that you can. For example, determining the appropriate dosage for a pediatric patient is the body weight, age and model, such as the age of the patient, the ontology of the clearance pathway of the compound of formula I, a pharmaceutically acceptable salt thereof, or a combination thereof, and the body surface area (BSA ), which can be used to establish a pharmacokinetic approach for dosing that can be determined using known methods including Simcyp® Pediatric Simulation Modeling (CERTARA, Princeton, NJ).

2. Polymorph

The present disclosure also relates to (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1 -Trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide crystalline form and pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising crystalline forms of compounds of formula I, of compounds of formula I It relates to methods of making crystalline forms, and the use of crystalline forms of compounds of formula (I) in the treatment and prevention of diseases that can be treated with BTK kinase inhibitors, including BTK-associated diseases and disorders.

Polymorphs of the compounds of formula I are provided herein. Forms include, for example, the free base, solvates, hydrates, salts and non-solvated forms of the compounds of formula I, including, for example, polymorph Form A. In some embodiments, the polymorphic form of the compound of Formula I is a pharmaceutically acceptable salt.

Form A

One such polymorph is a polymorph of the compound of formula I known as Form A. In some embodiments, Form A has an XRPD pattern obtained by CuKα1-radiation, with peaks at °2θ values of at least 11.9±0.2, 15.8±0.2, and 16.2±0.2. In some embodiments, Form A has an XRPD pattern with peaks at °2θ values of at least 11.9±0.2, 15.8±0.2, 16.2±0.2, 18.3±0.2, and 19.0±0.2. In some embodiments, Form A has an XRPD pattern with peaks at °2θ values of at least 11.9±0.2, 15.8±0.2, 16.2±0.2, 18.3±0.2, 19.0±0.2, 20.5±0.2, and 23.8±0.2. In some embodiments, Form A is at least 9.5±0.2, 11.9±0.2, 15.8±0.2, 16.2±0.2, 18.3±0.2, 19.0±0.2, 20.1±0.2, 20.5±0.2, 23.8±0.2, and 25.7±0.2 degrees. It has an XRPD pattern with a peak at the 2θ value. For example, in some embodiments, Form A is at least 9.5±0.2, 11.1±0.2, 11.9±0.2, 15.8±0.2, 16.2±0.2, 18.3±0.2, 19.0±0.2, 20.1±0.2, 20.5±0.2, 23.8 It has an XRPD pattern with peaks at °2θ values of ±0.2, 25.0±0.2, and 25.7±0.2.

In some embodiments, a composition comprising polymorph Form A is provided herein. In some embodiments, the composition can be substantially pure. For example, the composition has a purity of at least about 90%. In some embodiments, the composition has a purity of at least about 95%. In some embodiments, the composition has a purity of at least about 98%. For example, the composition is at least 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8% or 99.9 It can have a purity of %. In some embodiments, the composition is substantially free of other forms of the compound of formula (I). In some embodiments, the composition contains less than about 15% by weight of other forms of the compound of formula (I). For example, the composition comprises 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6% by weight of one or more different forms of the compound of formula (I). It may contain less than 1% by weight, 5%, 4%, 3%, 2%, 1% by weight. For example, the composition may contain less than about 15% amorphous form.

In some embodiments, provided herein is polymorph Form A that exhibits an endotherm observed at about 185-195° C., eg, at about 189.9° C., as measured by DSC on absorbed water.

In some embodiments, polymorph Form A of the compound of Formula I exhibits a weight loss of about 0.14% from the onset of heating to about 150° C. as measured by TGA.

Methods of making polymorph Form A are also provided herein. In some embodiments, polymorph Form A of the compound of formula I is prepared by dissolving the compound of formula I in a polar protic solvent to form a solution of the compound of formula I. In some embodiments, the polar protic solvent is methanol. In some embodiments, the method further comprises heating the solution of the compound of Formula I to about 55°C. In some embodiments, water is added to the solution of the compound of formula (I) over about 2 hours at a rate of about 5 mL/min. In some embodiments, the compound of formula I is precipitated from solution to provide a suspension comprising a solid of the compound of formula I suspended in a solvent. In some embodiments, the method further comprises cooling the suspension to about 15° C. at a rate of about 10° C./hour. In some embodiments, the method further comprises stirring the cooled suspension at room temperature for about 10-20 hours, such as about 15 hours. In some embodiments, the method comprises isolating the solid of the compound of formula (I) from the suspension via filtration. In some embodiments, the solid of the compound of formula (I) is dried. In some embodiments, the solid of the compound of formula I is dried under vacuum. In some embodiments, the solid is dried at about 55°C.

In some embodiments, polymorph Form A of a compound of formula (I) is prepared by adding a compound of formula (I) to a polar protic solvent to form a mixture. In some embodiments, the mixture is heated until a solution is formed. In some embodiments, the polar protic solvent is isopropanol, ethanol, water, or a combination thereof. In some embodiments, the polar protic solvent is isopropanol. In some embodiments, the solution is slowly cooled to room temperature. In some embodiments, the solution is abrasive filtered and then cooled. In some embodiments, the solution is added to a reactor containing water. In some embodiments, the solution is added to the reactor after abrasive filtration. In some embodiments, the compound of formula I is precipitated from solution to provide a suspension comprising a solid of the compound of formula I suspended in a solvent. In some embodiments, the method comprises isolating the solid of the compound of formula (I) from the suspension via filtration. In some embodiments, the solid of the compound of formula (I) is dried. In some embodiments, the solid of the compound of formula I is dried under vacuum. In some embodiments, the solid is dried at about 55°C.

In some embodiments, compounds of formula I are crystallized using polar protic and nonpolar solvents such as ethanol or ethyl acetate and heptane. In some embodiments, polymorph Form A of a compound of formula (I) is prepared by adding a compound of formula (I) to a polar protic solvent to form a mixture. In some embodiments, the mixture is heated until a solution is formed. In some embodiments, the mixture is heated to about 70°C. In some embodiments, the polar protic solvent is ethanol. In some embodiments, the solution is cooled and charged with Form A seeds of the compound of formula (I) to form a charged solution. In some embodiments, the solution is cooled to about 59°C. In some embodiments, the solution is abrasive filtered and then cooled. In some embodiments, the charged solution is cooled to about 55° C. and heptane is added to the charged solution. In some embodiments, heptane is added dropwise. In some embodiments, heptane is added dropwise over about 4 hours. In some embodiments, the compound of formula I is precipitated from a charged solution to provide a suspension comprising a solid of the compound of formula I suspended in a solvent. In some embodiments, the suspension is cooled to about 15°C. In some embodiments, the suspension is cooled to about 15° C. over about 1 hour. In some embodiments, the method comprises isolating the solid of the compound of formula (I) from the suspension via filtration. In some embodiments, the solid of the compound of formula (I) is dried. In some embodiments, the solid of the compound of formula I is dried under vacuum. In some embodiments, the solid is dried at about 55°C.

In some embodiments, compounds of formula I are crystallized using polar protic and nonpolar solvents such as ethanol or ethyl acetate and heptane. In some embodiments, polymorph Form A of a compound of formula (I) is prepared by adding a compound of formula (I) to a polar protic solvent to form a mixture. In some embodiments, the mixture is heated until a solution is formed. In some embodiments, the mixture is heated to about 75°C. In some embodiments, the polar protic solvent is ethyl acetate. In some embodiments, the solution is cooled and charged with Form A seeds of the compound of formula (I) to form a charged solution. In some embodiments, the solution is charged after cooling to about 45°C. In some embodiments, the solution is abrasive filtered and then cooled. In some embodiments, heptane is slowly added to the charged solution. In some embodiments, the compound of formula I is precipitated from solution to provide a suspension comprising a solid of the compound of formula I suspended in a solvent. In some embodiments, the suspension is incubated to form an incubated suspension. In some embodiments, the suspension is incubated at 45°C. In some embodiments, the suspension is incubated overnight. In some embodiments, the incubated suspension is cooled. In some embodiments, the incubated suspension is cooled to about 24°C. In some embodiments, the method comprises isolating a solid of the compound of formula (I) from the incubated suspension via filtration. In some embodiments, the solid of the compound of formula (I) is dried. In some embodiments, the solid of the compound of formula I is dried under vacuum. In some embodiments, the solid is dried at about 55°C.

Form B and C

In addition to Form A, other forms of compounds of formula I have been observed. Form B is observed as a mixture with Form A. The DSC of the mixture of Forms A and B shows little exotherm with an onset temperature of approximately 120° C. and an onset temperature of the melt (probably the melt of Form B) at approximately 145° C. Following the melt at approximately 145° C., there is an exothermic event due to the conversion of the melt to Form A. The endothermic event with an onset temperature of 180° C. is due to the melt of Form A. However, a pure sample of Form B is required to determine the DSC curve for Form B.

In some embodiments, Form B of the compound of formula I is prepared as a mixture with Form A by 1) dissolving the compound of formula I in methanol to form a solution of the compound of formula I and 2) stirring the solution. In some embodiments, the solution is stirred at a temperature of about 20° C. to about 30° C. In some embodiments, the solution is stirred at a temperature of about 25°C. In some embodiments, the compound of formula I is precipitated from solution to provide a suspension comprising a solid of the compound of formula I suspended in a solvent. In some embodiments, the method comprises isolating the solid of the compound of formula (I) via filtration. In some embodiments, the solid of the compound of formula (I) is dried. In some embodiments, the solid of the compound of formula I is dried under vacuum. In some embodiments, the solid is dried at about 55°C.

Form C is a hemi-1,4-dioxane solvate formed from crystallization of a compound of formula I in 1,4-dioxane. The DSC curve of Form C shows the endotherm at 40-110° C. associated with the loss of 1,4-dioxane. The endothermic event is followed by a few exothermic events, followed by the endothermic of the melt due to the melting of Form A. Desolvation can take place to give a homogeneous desolvate or a different physical form before it can be converted to polymorph Form A.

In some embodiments, Form C of the compound of formula I is prepared by 1) dissolving the compound of formula I in 1,4-dioxane to form a solution of the compound of formula I and 2) stirring the solution. In some embodiments, the solution is stirred at a temperature of about 20° C. to about 30° C. In some embodiments, the solution is stirred at a temperature of about 25°C. In some embodiments, the compound of formula I is precipitated from solution to provide a suspension comprising a solid of the compound of formula I suspended in a solvent. In some embodiments, the method comprises isolating the solid of the compound of formula (I) via filtration. In some embodiments, the solid of the compound of formula (I) is dried. In some embodiments, the solid of the compound of formula I is dried under vacuum. In some embodiments, the solid is dried at about 55°C.

The 2-theta value of the XRPD pattern for the crystalline form of the compound of formula (I) and its pharmaceutically acceptable salts may vary slightly from instrument to instrument and also with variation and batch to batch variation in the sample formulation, so the values recited are absolute values. It will be understood that it should not be interpreted as. It will be understood that the peak position in the XRPD pattern is reported in terms of the angular position (2 theta) with an acceptable variation of ±0.2° 2θ. A variation of ±0.2° 2θ is intended to be used when comparing two powder XRPD patterns. In fact, if the diffraction pattern peak from one pattern is assigned a range of angular positions (2 theta) that is ±0.2° of the measured peak position, and if these ranges of the peak positions overlap, then the two peaks are at the same angular position. Is considered to have. For example, if a peak from one pattern is determined to have a position of 11.0° 2θ, for the purposes of comparison an allowable variation causes the peak to be assigned a position in the range of 10.8°-11.2° 2θ. It will also be understood that the intensities presented in the XRPD traces included herein are exemplary and that the relative intensities of the peaks may vary depending on the orientation effect so that they are not intended to be used for absolute comparison. Additionally, it should be further understood that some variation in peak intensity from that presented in the XRPD trace is allowed for comparison purposes. Accordingly, the phrase “XRPD pattern substantially identical to that shown in FIG. 1” should be understood to mean that at least 90% of the peaks shown in FIG. 1 are present for comparison purposes.

The compounds provided herein may also contain non-natural proportions of atomic isotopes at one or more of the atoms that make up such compounds. That is, an atom includes all isotopes and isotope mixtures of that atom, especially when mentioned in connection with the compounds of formula (I), such as naturally occurring isotopes having a natural abundance. For example, when hydrogen is mentioned, it is understood to refer to ¹ H, ² H, ^{3 H or mixtures thereof;} When carbon is mentioned it is understood to refer to ¹² C, ¹³ C, ^{14 C or mixtures thereof;} When nitrogen is mentioned it is understood to refer to ¹⁴ N, ^{15 N or mixtures thereof;} When oxygen is mentioned, it is understood to refer to ¹⁶ O, ¹⁷ O, ^{18 O or mixtures thereof.} All isotopic modifications of the compounds provided herein are intended to be encompassed within the scope of the present invention.

For illustrative purposes, Scheme 1 shows a general method of preparing the compounds provided herein as well as the main intermediates. For a more detailed description of the individual reaction steps, see, for example, International Patent Publication No. WO 2017/103611, which is incorporated herein by reference in its entirety. One of ordinary skill in the art will recognize that other synthetic routes may be used to synthesize the compounds. Although specific starting materials and reagents are shown and discussed in the schemes below, other starting materials and reagents can be readily substituted to provide various derivatives and/or reaction conditions.

Scheme 1

Scheme 1 shows a scheme for the synthesis of compounds of formula I

3. Treatment method

The ability of compounds of formula I, polymorphic forms and pharmaceutically acceptable salts thereof, to act as BTK inhibitors can be demonstrated by the assays described in International Patent Application Publication WO 2017/103611 as well as Example 1.

In some embodiments, compounds of Formula I provided herein exhibit potent and selective BTK inhibition. For example, compounds of formula I exhibit nanomolar potency against wild-type BTK and BTK kinases encoded by BTK genes comprising BTK kinase inhibitor resistance mutations, including, for example, C481S. In some embodiments, inhibition of C481S is similar to that observed for wild type BTK.

In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, selectively targets BTK kinase. For example, a compound of Formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, can selectively target BTK kinase over another kinase or non-kinase target. In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, is BRK, CSK, ERBB4, FYN, MEK1, MEK2, TEC, TXK, YES1, BMX, BLK, EGFR, ITK, SRC. , JAK1, JAK2 and JAK3 selectively targets BTK kinase compared to one or more of them. In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, selectively targets BTK kinase over TEC kinase.

In some embodiments, a compound of Formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, exhibits at least 30-fold selectivity for BTK kinase over another kinase. For example, a compound of Formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, is at least 40-fold selectivity for BTK kinase over another kinase; At least 50 times selectivity; At least 60 times selectivity; At least 70 times selectivity; At least 80 times selectivity; At least 90 times selectivity; At least 100 times selectivity; At least 200 times selectivity; At least 300 times selectivity; At least 400 times selectivity; At least 500 times selectivity; At least 600 times selectivity; At least 700 times selectivity; At least 800 times selectivity; At least 900 times selectivity; Or at least 1000 times selectivity. In some embodiments, a compound of Formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, exhibits at least 100-fold selectivity for BTK kinase over another kinase. In some embodiments, selectivity for a BTK kinase over another kinase is measured in a cell assay (eg, a cell assay as provided herein). In some embodiments, a compound of Formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, exhibits lower off-target toxicity due to its selectivity for BTK kinase compared to another kinase.

A compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical composition thereof, can be treated with a BTK kinase inhibitor, such as BTK-associated diseases and disorders, It is useful, for example, to treat proliferative disorders such as cancer, such as hematologic cancer and solid tumors, and inflammatory and autoimmune disorders such as rheumatoid arthritis or lupus.

To a subject in need of treatment of cancer (e.g., BTK-associated cancer) a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical thereof Provided herein are methods of treating cancer (eg, BTK-associated cancer) in said subject comprising administering a composition. For example, a) detecting dysregulation of the expression or activity or level of a BTK gene, a BTK kinase, or any of these in a sample from a subject in need of treatment of a BTK-associated cancer; And b) administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. Provided herein are methods of treating.

In some embodiments, the dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of these comprises increased expression of the BTK kinase, increased transcription of the BTK gene, or increased activation or phosphorylation of the BTK kinase. do. In some embodiments, the dysregulation of the expression or activity or level of the BTK gene, BTK protein, or any of these is at least as compared to a gene mutation (e.g., a BTK gene translocation that causes the expression of a fusion protein, a wild-type BTK protein). A deletion in the BTK gene that causes the expression of the BTK protein containing a deletion of one amino acid, or a mutation in the BTK gene that causes the expression of the BTK protein with one or more point mutations, or in the BTK protein compared to the wild-type BTK protein. An alternative spliced version of BTK mRNA that produces a BTK protein that causes deletion of at least one amino acid), or an autocrine activity resulting from overexpression of the BTK protein or overexpression of the BTK gene in cells, It may be a BTK gene amplification that causes an increase in the pathogenicity of the activity of the kinase domain of the BTK protein (eg, a constitutively active kinase domain of the BTK protein) in the cell. In some embodiments, the dysregulation of the expression or activity or level of the BTK gene, BTK protein, or any of them has increased activity or constitutively active compared to the protein encoded by the BTK gene that does not contain the mutation. It may be a mutation in the BTK gene encoding the phosphorus BTK protein. Non-limiting examples of BTK mutations (and fusions) are described in Table 1. Further examples of dysregulation of the expression or activity or level of the BTK gene, BTK protein, or any of these are BTK inhibitor resistance mutations. Non-limiting examples of BTK resistance mutations are described in Tables 2 and 3.

In some embodiments, the dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of these is followed by an activating mutation in the BCR complex or downstream signaling component, a microbial antigen or an autoantigen present in the tissue microenvironment. BCR stimulation, or a result of ligand-independent tonic BCR signaling that causes a pathogenic increase in the expression or activation of BTK protein. For example, dysregulation of the expression or activity or level of the BTK gene, BTK protein, or any of these may be the result of a gene mutation in the BCR signaling pathway protein (e.g., BCR causing the expression of a fusion protein. Signal transduction pathway gene translocation, a deletion in the BCR signaling pathway gene, or one or more point mutations resulting in the expression of the BCR signaling pathway protein comprising a deletion of at least one amino acid compared to the wild-type BCR signaling pathway protein. A mutation in the BCR signaling pathway gene that causes the expression of the BCR signaling pathway protein, or a BCR signaling pathway protein that causes the deletion of at least one amino acid in the BCR signaling pathway protein compared to a wild-type BCR signaling pathway protein is created. An alternative spliced version of the BCR signaling pathway protein mRNA). Non-limiting examples of BCR signaling pathway mutations are described in Table 4.

In some embodiments, the compound of Formula I is in polymorphic form. In some embodiments, the compound of formula I is polymorph Form A.

In some embodiments, the spray-dried dispersion comprises a compound of Formula I and a HPMCAS polymer. In some embodiments, the pharmaceutical composition comprises a spray-dried dispersion of a compound of Formula I and an HPMCAS polymer. In some embodiments, the HPMCAS polymer is HPMCAS-MG.

The compounds of formula I, or pharmaceutically acceptable salts, amorphous or polymorphic forms thereof, spray-dried dispersions thereof, or pharmaceutical compositions thereof are also useful for treating BTK-associated cancers.

In some embodiments of any of the methods or uses described herein, the cancer (eg, BTK-associated cancer) is a hematological cancer. In some embodiments of any of the methods or uses described herein, the cancer (eg, BTK-associated cancer) is a solid tumor. In some embodiments of any of the methods or uses described herein, the cancer (eg, BTK-associated cancer) is a B-cell malignancy. In some embodiments of any of the methods or uses described herein, the cancer (e.g., BTK-associated cancer) is Hodgkin's lymphoma, diffuse versus B cell lymphoma (DLBCL) (e.g., activated B cell-like DLBCL (ABC-DLBCL)), follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma (e.g., extranodal marginal B-cell lymphoma, splenic marginal zone lymphoma), Burkitt's lymphoma, Waldenstrom macroglobulinemia (lymphoplasmocytic lymphoma (LPL) )), primary central nervous system lymphoma, small lymphocytic lymphoma, chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), B-cell prolymphocytic leukemia, precursor B-lymphoblastic leukemia, hairy cell leukemia Acute myelogenous leukemia (AML), chronic myelogenous leukemia, multiple myeloma, plasma cell myeloma, plasmacytoma, bone cancer, bone metastasis, breast cancer, gastroesophageal cancer, pancreatic cancer, ovarian cancer, prostate cancer, lung cancer, colon cancer, uterine cancer, hepatocellular cancer, two It is cervical cancer or glioma.

In some embodiments, the hematologic cancer (e.g., a hematologic cancer that is a BTK-associated cancer) is leukemia, lymphoma (non-Hodgkin's lymphoma), Hodgkin's disease (also called Hodgkin's lymphoma), and myeloma, such as Acute Lymphocytic Leukemia (ALL), Acute Myeloid Leukemia (AML), Acute Promyelocytic Leukemia (APL), Chronic Lymphocytic Leukemia (CLL), Chronic Myeloid Leukemia (CML), Chronic Myelomonocytic Leukemia (CMML), Chronic Neutrophil Constituent leukemia (CNL), acute undifferentiated leukemia (AUL), anaplastic large cell lymphoma (ALCL), prolymphocytic leukemia (PML), pediatric myelomonocytic leukemia (JMML), adult T-cell ALL, with 3-line myelodysplasia AML (AML/TMDS), mixed lineage leukemia (MLL), myelodysplastic syndrome (MDS), myeloproliferative disorder (MPD), diffuse versus B cell lymphoma (DLBCL) (e.g., activated B cell-like DLBCL ( ABC-DLBCL)), follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma (e.g., extranodal marginal B-cell lymphoma, splenic marginal zone lymphoma), Burkitt's lymphoma, Waldenstrom's macroglobulinemia (lymphoplasmocytic lymphoma (LPL) ), primary central nervous system lymphoma, small lymphocytic lymphoma, precursor B-lymphoblastic leukemia, hairy cell leukemia, chronic myelogenous leukemia, anaplastic large cell lymphoma, MALT lymphoma, plasma cell myeloma, plasmacytoma and multiple myeloma (MM) It is selected from the group consisting of. Additional examples of hematologic cancers include myeloproliferative disorders (MPD), such as polycythemia vera (PV), thrombocytopenia (ET) and idiopathic primary myelofibrosis (IMF/IPF/PMF). In one embodiment, the hematologic cancer (eg, a hematologic cancer that is a BTK-associated cancer) is mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstrom macroglobulinemia, or marginal zone lymphoma.

In some embodiments, the BTK-associated cancer has not undergone transformation. Non-limiting examples of transformations in BTK-associated cancers include Richter transformation, prolymphocyte transformation (e.g., prolymphocyte transformation of CLL), transformed non-Hodgkin's lymphoma and blastoid lymphoma (e.g. For example, blastoid variant mantle cell lymphoma).

In some embodiments, the BTK-associated cancer is not a cancer with known central nervous system involvement by lymphoma.

In some embodiments, the cancer (eg, BTK-associated cancer) is a solid tumor. Examples of solid tumors (e.g., solid tumors that are BTK-associated cancers) include, for example, bone cancer, bone metastasis, breast cancer, gastric-esophageal cancer, pancreatic cancer, ovarian cancer, prostate cancer, lung cancer, colon cancer, uterine cancer, hepatocellular cancer, two Including cervical cancer and glioma. See, for example, Campbell, et al., Journal of Clinical Medicine, 2018, 7(4): 62 and Zucha et al., Oncotarget. 6(15):13255-68, 2015], each of which is incorporated herein by reference in its entirety.

In some embodiments, the B-cell malignancies are B-cell non-Hodgkin's lymphoma, Hodgkin's lymphoma, or B-cell leukemia. In some embodiments, the B-cell malignancies are Hodgkin's lymphoma, diffuse large B cell lymphoma (DLBCL) (e.g., activated B cell-like DLBCL (ABC-DLBCL)), follicular lymphoma, mantle cell lymphoma, Marginal zone lymphoma (e.g., extranodal marginal B-cell lymphoma, splenic marginal zone lymphoma), Burkitt's lymphoma, Waldenstrom macroglobulinemia (Lymphplasmocytic lymphoma (LPL)), primary central nervous system lymphoma, small lymphocytic lymphoma, chronic lymph Constituent leukemia, acute lymphoblastic leukemia (ALL), B-cell prolymphocytic leukemia, precursor B-lymphoblastic leukemia or hairy cell leukemia.

In some embodiments, the subject does not have active uncontrolled autoimmune cytopenia. In some embodiments, the subject has not been diagnosed with autoimmune cytopenia. In some embodiments, the subject does not have a history of clinically significant uncontrolled heart, cardiovascular disease, or myocardial infarction within 6 months of initiating treatment as described herein. In some embodiments, the subject has not been diagnosed with a heart or cardiovascular disease. In some embodiments, the subject did not have a myocardial infarction. In some embodiments, the subject does not have a clinically significant active malabsorption syndrome. In some embodiments, the subject has not been diagnosed with malabsorption syndrome. In some embodiments, the subject is not being treated with a strong cytochrome P450 3A4 (CYP3A4) inhibitor or inducer during any treatment as described herein. In some embodiments, the subject has not been treated with a proton pump inhibitor within 7 days of starting any of the treatments described herein. In some embodiments, the subject does not have an active second malignancy. In some embodiments, the subject has an active second malignancy in remission and the subject has an life expectancy of> 2 years.

In some embodiments, the subject is human. In some embodiments of any of the methods or uses described herein, the subject is a BTK-inhibitor naive. In other embodiments of any of the methods or uses described herein, the subject is not a BTK-inhibitor naive.

Thus, to a subject diagnosed with or identified as having a BTK-associated cancer, e.g. any of the exemplary BTK-associated cancers disclosed herein, a therapeutically effective amount of a compound of formula I as defined herein or a pharmaceutically acceptable Also provided herein is a method of treating a subject comprising administering a salt, amorphous or polymorphic form, a spray-dried dispersion thereof, or a pharmaceutical composition thereof.

Dysregulation of the expression or activity or level of BTK kinase, BTK gene, or any of them (eg, one or more) can contribute to tumorigenesis. For example, the dysregulation of the expression or activity or level of a BTK kinase, a BTK gene, or any of these may be overexpression, activation, amplification, mutation or translocation of a BTK kinase, BTK gene or BTK kinase domain. In some embodiments, the dysregulation of the BTK kinase is due to aberrant cellular signaling and/or dysregulated autocrine/perisecretory signaling (e.g., compared to a control non-cancerous cell) wild-type BTK in mammalian cells. It may be increased expression (eg, increased level) or increased activation (eg, increased phosphorylation) of the kinase. In some embodiments, the increased expression of BTK kinase may be due to increased transcription of the BTK gene. In some embodiments, the dysregulation of the BTK kinase is a mammalian cell (e.g., compared to a control non-cancerous cell) due to, for example, aberrant cell signaling and/or dysregulated autocrine/perisecretory signaling. May be increased expression (eg, increased levels) of wild-type BTK kinase in. In some embodiments, the dysregulation of the BTK kinase may be over-activation (eg, compared to a control non-cancerous cell). In some embodiments, over-activation may be due to increased phosphorylation of BTK. In some embodiments, mutations in the BTK gene may include mutations in BTK ligand-binding sites, extracellular domains, kinase domains, and regions involved in protein:protein interactions and downstream signaling. In some embodiments, the mutation (e.g., activating mutation) in the BTK gene is one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9 or 10) amino acids in the kinase domain. It can lead to the expression of BTK kinases with substitutions (eg, one or more amino acid substitutions). In some embodiments, the mutation may be a gene amplification of the BTK gene. In some embodiments, a mutation in the BTK gene (e.g., an activating mutation) is at least one amino acid (e.g., at least 2, at least 3, at least 4, at least 5, at least 6, at least 7) compared to the wild-type BTK protein. , At least 8, at least 9, at least 10, at least 12, at least 14, at least 16, at least 18, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45 or at least 50 amino acids) Or it can induce the expression of the BTK receptor. In some embodiments, the mutation in the BTK gene (e.g., an activating mutation) is at least 1 amino acid (e.g., at least 2, at least 3, at least 4, at least 5, at least 6, BTK with at least 7, at least 8, at least 9, at least 10, at least 12, at least 14, at least 16, at least 18, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45 or at least 50 amino acids) Can trigger the expression of kinases. The translocation may include a gene translocation that causes the expression of a fusion protein comprising a BTK kinase domain and a fusion partner. For example, the fusion protein can have increased kinase activity compared to the wild type BTK protein. Other dysregulations may include BTK mRNA splice variants. In some embodiments, the wild type BTK protein is an exemplary wild type BTK protein described herein.

In some embodiments, the dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of these comprises overexpression of the wild-type BTK kinase. In some embodiments, the dysregulation of the expression or activity or level of the BTK gene, BTK kinase protein, or any of them is a chromosome comprising a BTK gene or a portion thereof, e.g., a kinase domain portion or a portion capable of exhibiting kinase activity. Includes overexpression, activation, amplification or mutation in a fragment.

In some embodiments, the dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of them is one or more deletions (e.g., deletions of amino acids at position 4), insertions or point mutations in the BTK kinase. Include(s). In some embodiments, the dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of these comprises deletion of one or more residues from the BTK kinase that causes constitutive activity of the BTK kinase domain.

In some embodiments, dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of these, results in the production of a BTK kinase with one or more amino acid substitutions, insertions or deletions compared to wild-type BTK kinase. At least one point mutation in the gene (see, for example, the point mutations listed in Table 1).

Table 1. BTK kinase protein amino acid substitution/insertion/deletion ^A

^A presented BTK kinase mutations may be activating mutations and/or confer increased resistance of BTK kinase to BTK kinase inhibitors and/or multi-kinase inhibitors (MKI) compared to, for example, wild-type BTK kinase.

^{1 See} Krysiak et al., Blood. 129(4):473-483, 2017].

^{2 See} Johnson et al., ACS Chem. Biol. 11(10):2897-2907, 2016].

^{3 See} Maddocks et al., JAMA Oncol. 1(1):80-7, 2015].

^{4 See} Chang et al., J. Clin. Oncol. 31(15): 7014-7014, 2013].

^{5 See} Xu et al. Blood. 129(18):2519-2525, 2017].

^{6 See} Xu et al. Blood. Abstract Number: 756. Meeting Info: 58th Annual Meeting of the American Society of Hematology, ASH 2016. San Diego, CA, United States, 2016].

^{7 See} Scherer et al., Abstract Number: 1752. Meeting Info: 58th Annual Meeting of the American Society of Hematology, ASH 2016. San Diego, CA, United States, 2016.

^{8 See} Sharma et al., Oncotarget. 7(42): 68833-68841, 2016].

In some embodiments, the dysregulation of the expression or activity or level of the BTK gene, BTK kinase protein, or any of these comprises one or more chromosomal translocations or inversions resulting in a BTK gene fusion. In some embodiments, the dysregulation of the expression or activity or level of the BTK gene, BTK kinase protein, or any of them is a fusion protein in which the expressed protein contains residues from a non-BTK partner protein and is a minimal functional BTK kinase domain. It is the result of gene translocation, including.

Non-limiting examples of BTK fusion proteins are shown in Table 1a.

Table 1a. Exemplary BTK Fusion Partners and Cancer.

In some embodiments, the dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of these comprises an alternatively spliced variant of BTK mRNA. In some embodiments, the alternatively spliced BTK mRNA produces a BTK kinase in which at least one residue is deleted (compared to wild type BTK kinase) resulting in constitutive activity of the BTK kinase domain. An example of a BTK kinase, an alternatively spliced variant of the wild-type BTK kinase, is p65BTK containing a first exon that is different from the wild-type BTK kinase, and the translation of p65BTK is putatively initiated in exon 4 instead of exon 2 as in wild-type BTK kinase. It is possible to start at the codon (Grassilli et al., Oncogene. 35(33):4368-78, 2016), which is incorporated herein by reference in its entirety). In some embodiments, p65BTK is expressed in colon cancer.

In some embodiments, the dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of these comprises BTK mRNA transcribed from an alternative promoter compared to wild type BTK kinase, which is compared to wild type BTK kinase. At least one amino acid at the N-terminus of the BTK kinase (e.g., at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 12, at least 14, at least 16, at least 18, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50 amino acids or at least 100 amino acids) are added to produce a BTK kinase. An example of a BTK kinase translated from an alternative promoter induces a BTK kinase with an N-terminal extension of 34 amino acids compared to a wild type BTK kinase and a different first exon due to alternative-splicing compared to a wild type BTK kinase. BTK-C with different start codons (Eifert et al., Genes Chromosomes Cancer. 52(10):961-75, 2013 and Kokabee et al. Cancer Biol. Ther. 16(11):1604) -15, 2015] (each of which is incorporated herein by reference in its entirety)). In some embodiments, BTK-C is expressed in prostate cancer or breast cancer.

In some embodiments, the dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of them is within the BTK gene resulting in the production of a BTK kinase with one or more amino acids inserted or removed compared to wild-type BTK kinase. At least one point mutation in the BTK gene that causes the production of a BTK kinase with one or more amino acid substitutions or insertions or deletions. In some cases, the resulting BTK kinase is more resistant to inhibition of its phosphotransferase activity by one or more first BTK kinase inhibitor(s) compared to a wild-type BTK kinase or a BTK kinase that does not contain the same mutation. . Such mutations optionally (e.g., compared to cancer cells or tumors that do not contain a specific BTK inhibitor resistance mutation) for treatment with a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, BTK It does not reduce the susceptibility of cancer cells or tumors with kinases. _{In this embodiment, the BTK inhibitor resistance mutation is increased V max} when in the presence of the first BTK kinase inhibitor compared to a wild-type BTK kinase or a BTK kinase that does not have the same mutation in the presence of the same first BTK kinase inhibitor. , A decreased K _{m for ATP, and an increased K D} for the first BTK kinase inhibitor. In other embodiments, the dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of these, has one or more amino acid substitutions compared to the wild-type BTK kinase and does not comprise a wild-type BTK kinase or the same mutation. And at least one point mutation in the BTK gene that results in the production of a BTK kinase with increased resistance to a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof compared to. In this embodiment, the BTK inhibitor resistance mutation is a compound of formula I or a BTK kinase that does not have the same mutation in the presence of a wild-type BTK kinase or a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof. BTK kinases with one or more _{of increased V max} , decreased K _m , and decreased K _D in the presence of a pharmaceutically acceptable salt, amorphous or polymorphic form thereof can be induced.

Examples of BTK inhibitor resistance mutations include, for example, gatekeeper residues (e.g., amino acid position 474 in wild-type BTK kinase), P-loop residues, residues in or near DFG motifs, and ATP interstitial solvent front amino acid residues. Point mutations, insertions or deletions within and near the ATP binding site in the tertiary structure of BTK kinase, but not limited thereto. Further examples of these types of mutations include, but are not limited to, residues in the activation loop, residues near or interacting with the activation loop, residues that contribute to the active or inactive enzymatic conformation, and/or Includes changes in residues that may affect drug binding, including mutations, deletions and insertions in loops and in C-helixes that proceed through the C-helix. In some embodiments, the wild type BTK protein is an exemplary wild type BTK kinase described herein. Certain residues or regions of residues that can be changed (and are BTK inhibitor resistance mutations) include, but are not limited to, those listed in Table 2, wherein the numbering refers to the human wild-type BTK protein sequence (e.g., SEQ ID NO: 1 ). As one of ordinary skill in the art will appreciate, the amino acid position in the reference protein sequence corresponding to a specific amino acid position in SEQ ID NO: 1 is determined by aligning the reference protein sequence with SEQ ID NO: 1 (e.g. , Can be determined using a software program such as ClustalW2). Changes to these residues can include single or multiple amino acid changes, insertions flanking within or to the sequence, and deletions flanking within or to the sequence. Also, the literature [J. Kooistra, G. K. Kanev, O. P. J. Van Linden, R. Leurs, I. J. P. De Esch, and C. De Graaf, "KLIFS: A structural kinase-ligand interaction database," Nucleic Acids Res., vol. 44, no. D1, pp. D365-D371, 2016], which is incorporated herein by reference in its entirety.

Exemplary sequence of mature human BTK protein (SEQ ID NO: 1)

In some embodiments, a compound of Formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof is a conventional drug treatment (e.g., other BTK kinase inhibitor; e.g. For example, by administration in combination for a first and/or second BTK kinase inhibitor) or as a subsequent or additional (e.g., follow-up) therapy to a BTK inhibitor resistance mutation (e.g., a first BTK inhibitor). Those that cause increased resistance to, e.g., a substitution at amino acid position 481, e.g. C481S, C481T, C481R, C481G and/or one or more BTK inhibitor resistance mutations listed in Tables 2 and 3). It is useful for treating subjects who develop it. Exemplary first and second BTK kinase inhibitors are described herein. In some embodiments, the first or second BTK kinase inhibitor is ibrutinib, PRN1008, PRN473, ABBV-105, AC0058, Acalabrutinib, Janubrutinib, Sfebrutinib, Poceltinib, Evobrutinib, M7583 , Tirabrutinib, CG'806, ARQ 531, BIIB068, Becabrutinib, AS871, CB1763, CB988, GDC-0853, RN486, Dasatinib, GNE-504, GNE-309, BCB-311, BTK Max, CT -1530, CGI-1746, CGI-560, LFM A13, TP-0158, dtrmwxhs-12, CNX-774 and LOU064. In some embodiments, the first or second BTK kinase inhibitor is a covalent inhibitor. Exemplary covalent inhibitors of BTK kinase include Ibrutinib, PRN1008, PRN473, ABBV-105, AC0058, Acalabrutinib, Janubrutinib, Sfebrutinib, Foceltinib, Evobrutinib, M7583 and Tirablutinib. However, it is not limited thereto. In some embodiments, the first or second BTK kinase inhibitor is a non-covalent inhibitor. Exemplary non-covalent inhibitors of BTK kinase include, but are not limited to, CG'806, ARQ 531, BIIB068, Becabrutinib, AS871, CB1763, CB988, GDC-0853, RN486 and Dasatinib.

In some embodiments, a compound of Formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof, comprises one or more BTK inhibitor resistance mutations (first or second BTK inhibitor Causing increased resistance to, e.g., a substitution at amino acid position 481, e.g. C481S, C481T, C481R and C481R, or e.g. a substitution at amino acid position 474, e.g. T474I, T474M and T474S It is useful for treating cancers that have been found to have ). Non-limiting examples of BTK inhibitor resistance mutations are listed in Table 2.

Table 2. Exemplary BTK Resistance Mutations

^{1 See} Krysiak et al., Blood. 129(4):473-483, 2017].

^{2 See} Johnson et al., ACS Chem. Biol. 11(10):2897-2907, 2016].

^{3 See} Maddocks et al., JAMA Oncol. 1(1):80-7, 2015].

^{4 See} Chang et al., J. Clin. Oncol. 31(15): 7014-7014, 2013].

^{5 See} Xu et al. Blood. 129(18):2519-2525, 2017].

^{6 See} Xu et al. Blood. Abstract Number: 756. Meeting Info: 58th Annual Meeting of the American Society of Hematology, ASH 2016. San Diego, CA, United States, 2016].

^{7 See} Scherer et al., Abstract Number: 1752. Meeting Info: 58th Annual Meeting of the American Society of Hematology, ASH 2016. San Diego, CA, United States, 2016.

^{8 See} Sharma et al., Oncotarget. 7(42): 68833-68841, 2016].

In other embodiments, the compound of Formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical composition thereof, comprises one or more BTK inhibitor resistance mutations (first or second BTK inhibitor Causing increased resistance to, e.g. a substitution at amino acid position 707 in PLCγ2, e.g. S707Y, S707P and S707F, or a substitution e.g. at amino acid position 251 in CARD11, e.g. L251P) It is useful for treating cancers that have been identified as having. Non-limiting examples of BTK inhibitor resistance mutations are listed in Table 3.

Table 3. Exemplary BTK Resistance Mutations

^{1 See} Landau et al., Nat. Commun. 8: 2185, 2017].

^{2 See} Xu et al., Blood. 129:2519-2525, 2017].

^{3 See} Woyach et al. N. Engl. J. Med. 370(24):2286-94, 2014].

⁴ US Patent Application Publication No. 2017/0360795A1.

^{5 See} Jones et al., Abstract Number: 3150. Meeting Info: American Association for Cancer Research Annual Meeting 2017, Washington, DC, United States, 2017.

⁶ U.S. Patent No. 9,885,086

⁷ [Yahiaoui et al., PLoS One. 12(2): e0171221, 2017].

In some embodiments, the dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of these is followed by an activating mutation in the BCR complex or downstream signaling component, a microbial antigen or an autoantigen present in the tissue microenvironment. BCR stimulation, or a result of ligand-independent tonic BCR signaling that causes a pathogenic increase in the expression or activation of BTK protein. In some embodiments, the dysregulation of the expression or activity or level of a BTK gene, BTK kinase, or any of these is a dysregulation of the expression or activity or level of a BCR signaling pathway gene, a BCR signaling pathway protein, or any of these. to be. In some embodiments, the dysregulation of the expression or activity or level of a BCR signaling pathway gene, a BCR signaling pathway protein, or any of these, is one or more activating mutations in the BCR complex or downstream signaling component, present in the tissue microenvironment. It is a ligand-independent tonic BCR signaling that causes continuous BCR stimulation by microbial antigens or autoantigens, or pathogenic increase in the expression or activation of BTK protein. For example, dysregulation of the expression or activity or level of the BTK gene, BTK protein, or any of these may be the result of a gene mutation in the BCR signaling pathway protein (e.g., BCR causing the expression of a fusion protein. Signal transduction pathway gene translocation, a deletion in the BCR signaling pathway gene, or one or more point mutations resulting in the expression of the BCR signaling pathway protein comprising a deletion of at least one amino acid compared to the wild-type BCR signaling pathway protein. A mutation in the BCR signaling pathway gene that causes the expression of the BCR signaling pathway protein, or a BCR signaling pathway protein that causes the deletion of at least one amino acid in the BCR signaling pathway protein compared to a wild-type BCR signaling pathway protein is created. An alternative spliced version of the BCR signaling pathway protein mRNA).

In some embodiments, the dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of these is compared to the wild-type BCR signaling pathway protein, and the production of a BCR signaling pathway protein with one or more amino acids inserted or removed. And at least one point mutation in the BCR signaling pathway gene that causes the production of a BCR signaling pathway protein having one or more amino acid substitutions or insertions or deletions in the BCR signaling pathway gene that causes In some embodiments, mutations in the BCR signaling pathway gene (e.g., activating mutations) are at least one (e.g., 2, 3, 4, 5, 6, 7, 8, 9 or 10) in the kinase domain. ) Of amino acid substitutions (eg, one or more amino acid substitutions). In some embodiments, the mutation may be a gene amplification of a BCR signaling pathway gene. In some embodiments, the mutation (e.g., activating mutation) in the BCR signaling pathway gene is at least one amino acid (e.g., at least 2, at least 3, at least 4, at least 5) compared to the wild-type BCR signaling pathway protein. , At least 6, at least 7, at least 8, at least 9, at least 10, at least 12, at least 14, at least 16, at least 18, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45 or at least 50 amino acids ) Lacking BCR signaling pathway proteins or BCR signaling pathway receptors. In some embodiments, the mutation (e.g., activating mutation) in the BCR signaling pathway gene is at least one amino acid (e.g., at least 2, at least 3, at least 4, at least 5) compared to the wild-type BCR signaling pathway protein. , At least 6, at least 7, at least 8, at least 9, at least 10, at least 12, at least 14, at least 16, at least 18, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45 or at least 50 amino acids ) Can induce the expression of the inserted BCR signaling pathway protein. Other dysregulations may include BCR signaling pathway mRNA splice variants. Non-limiting examples of BCR signaling pathway mutations are described in Table 4.

Table 4. Exemplary BCR signaling pathway mutations

¹ Cinar et al., Leukemia Research 37 (2013) 1271-1277.

^{2 See} David et al., Nature. 2010 Jan 7; 463(7277): 88-92].

^{3 See} Chin et al. Int J Mol Sci. 2017 Oct; 18(10): 2038].

⁴ Singh et al., Mol Cancer. 2018; 17: 57].

^{5 See} Sun et al., Blood, Vol. 128, No. 22, pp. 1058, Meeting Info. 58th Annual Meeting and Exposition of the American-Society-of-Hematology. San Diego, CA, USA. 2016].

In other embodiments, the dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of them has one or more amino acid substitutions compared to the wild-type BCR signaling pathway protein and has a wild-type BCR signaling pathway protein or the same mutation. BCR signal having increased resistance to a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical composition thereof compared to a BCR signaling pathway protein that does not contain It contains at least one point mutation in the BCR signaling pathway gene that causes the production of the transduction pathway protein.

Thus, a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof, is administered to a subject diagnosed with cancer (or confirmed to have cancer). Provided herein are methods of treating the subject comprising administering. Administering to a subject identified or diagnosed as having BTK-associated cancer a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. Also provided herein is a method of treating the subject, comprising. In some embodiments, the subject is a regulatory agency-approved, e.g., FDA-approved, for identifying dysregulation of the expression or activity or level of a BTK gene, BTK kinase, or any of these in a subject or a biopsy sample from a subject. Has been identified or diagnosed as having a BTK-associated cancer through the use of a tested or assay or by performing any of the non-limiting examples of assays described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is a BTK-associated cancer. For example, a BTK-associated cancer can be a cancer comprising one or more BTK inhibitor resistance mutations.

(a) detecting BTK-associated cancer in a subject in need of treatment of the cancer; And (b) administering to the subject a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. Also provided is a method of treating. Some embodiments of these methods further comprise administering to the subject another anticancer agent (eg, a second BTK inhibitor or immunotherapy). In some embodiments, the subject is previously treated with a first BTK inhibitor or previously treated with another anti-cancer treatment, such as at least partial resection of a tumor or radiation therapy. In some embodiments, the subject is a regulatory agency-approved, e.g., FDA-approved, for identifying dysregulation of the expression or activity or level of a BTK gene, BTK kinase, or any of these in a subject or a biopsy sample from a subject. It is determined to have a BTK-associated cancer through the use of a tested test or assay or by performing any of the non-limiting examples of the assays described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is a BTK-associated cancer. For example, a BTK-associated cancer can be a cancer comprising one or more BTK inhibitor resistance mutations. In some embodiments, the dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of these is the result of one or more mutations in the one or more BCR signaling pathway proteins. In some embodiments, the BCR signaling pathway protein is selected from the group consisting of Cyclin-D1, CARD11, CD79B, CD79A, MYD88, and combinations thereof.

Performing an assay on a sample obtained from the subject to determine whether the subject has a dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of these, and the BTK gene, BTK kinase, or any of these. Administration of a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form, spray-dried dispersion thereof or a pharmaceutical composition thereof to a subject determined to have dysregulation of the expression or activity or level of any Also provided is a method of treating a subject comprising the step of (eg, specifically or selectively administering). Some embodiments of these methods further comprise administering to the subject another anticancer agent (eg, a second BTK inhibitor or immunotherapy). In some embodiments of these methods, the subject is previously treated with a first BTK inhibitor or previously treated with another anti-cancer treatment, such as at least partial resection of the tumor or radiation therapy. In some embodiments, the subject is a subject suspected of having a BTK-related cancer, a subject presenting one or more symptoms of a BTK-related cancer, or a subject with an elevated risk of developing BTK-related cancer. In some embodiments, the assay uses next-generation sequencing, pyrosequencing, immunohistochemistry, immunoblot, or digested FISH analysis. In some embodiments, the assay is a regulatory agency-approved assay, eg, an FDA-approved kit. In some embodiments, the assay is a liquid biopsy. Additional non-limiting assays that can be used in these methods are described herein. Additional assays are also known in the art. In some embodiments, the dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of these comprises one or more BTK inhibitor resistance mutations.

Performing an assay (e.g., an in vitro assay) on a sample obtained from the subject to determine whether the subject has dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of them, Herein, the presence of a dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of these, confirms that the subject has a BTK-associated cancer. Also provided are compounds of formula I, or pharmaceutically acceptable salts, amorphous or polymorphic forms, spray-dried dispersions thereof, or pharmaceutical compositions thereof, for use in treating BTK-associated cancer in a subject. Performing an assay on a sample obtained from a subject to determine whether the subject has a dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of them, wherein the BTK gene, BTK kinase, or these Treating BTK-associated cancer in a subject identified or diagnosed as having BTK-associated cancer through a step wherein the presence of dysregulation of the expression or activity or level of any of the subjects is confirmed to have BTK-associated cancer Also provided is the use of a compound of formula (I) or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, or a spray-dried dispersion thereof for the manufacture of a medicament for Some embodiments of any of the methods or uses described herein are directed to a subject determined to have dysregulation of the expression or activity or level of a BTK gene, BTK kinase, or any of them through performing an assay. It further comprises the step of recording in the subject's clinical record (e.g., a computer readable medium) that the phase acceptable salt, amorphous or polymorphic form, a spray-dried dispersion thereof, or a pharmaceutical composition thereof should be administered. . In some embodiments, the assay uses next-generation sequencing, pyrosequencing, immunohistochemistry, immunoblot, or digested FISH analysis. In some embodiments, the assay is a regulatory agency-approved assay, eg, an FDA-approved kit. In some embodiments, the assay is a liquid biopsy. In some embodiments, the dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of these comprises one or more BTK inhibitor resistance mutations. In some embodiments, the dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of these is the result of one or more mutations in the one or more BCR signaling pathway proteins. In some embodiments, the BCR signaling pathway protein is selected from the group consisting of Cyclin-D1, CARD11, CD79B, CD79A, MYD88, and combinations thereof.

A compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray thereof for use in the treatment of cancer in a subject in need of treatment of cancer or in a subject identified or diagnosed with BTK-associated cancer Dried dispersions or pharmaceutical compositions thereof are also provided. The use of a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof or a spray-dried dispersion thereof for the manufacture of a medicament for the treatment of cancer in a subject identified or diagnosed with BTK-associated cancer Also provided. In some embodiments, the cancer is a BTK-associated cancer, eg, a BTK-associated cancer having one or more BTK inhibitor resistance mutations. In some embodiments, the subject is a regulatory agency-approved, e.g., FDA-approved, for identifying dysregulation of the expression or activity or level of a BTK gene, BTK kinase, or any of these in a biopsy sample from the subject or sample. It is identified or diagnosed as having BTK-associated cancer through the use of the kit. As provided herein, BTK-associated cancers include those described herein and known in the art.

In some embodiments of any of the methods or uses described herein, the subject has been identified or diagnosed as having a cancer having dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of these. In some embodiments of any of the methods or uses described herein, the subject has a tumor that is positive for dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of these. In some embodiments of any of the methods or uses described herein, the subject may be a subject having a tumor(s) that is positive for dysregulation of the expression or activity or level of a BTK gene, a BTK kinase, or any of these. In some embodiments of any of the methods or uses described herein, the subject can be a subject whose tumor has a dysregulation of the expression or activity or level of a BTK gene, a BTK kinase, or any of these. In some embodiments of any of the methods or uses described herein, the subject is suspected of having a BTK-associated cancer (eg, a cancer having one or more BTK inhibitor resistance mutations). In some embodiments of any of the methods or uses described herein, the subject is a BTK-inhibitor naive. In other embodiments of any of the methods or uses described herein, the subject is not a BTK-inhibitor naive. In some embodiments, a) detecting dysregulation of the expression or activity or level of a BTK gene, BTK kinase, or any of these in a sample from a subject in need of treatment of a BTK-associated cancer; And b) administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. Provided herein are methods of treating. In some embodiments, the dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of these comprises one or more fusion proteins. Non-limiting examples of BTK gene fusion proteins are described in Table 1a. In some embodiments, the dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of these comprises one or more BTK kinase protein point mutations/insertions/deletions. Non-limiting examples of BTK kinase protein point mutations/insertions/deletions are described in Table 1. In some embodiments, the BTK kinase protein point mutation/insertion/deletion is selected from the group consisting of T117P, T316A, T474I, T474M, T474S, C481S, C481S, C481T, C481G, C481R, L528W, P560L, R562W, R562G and F601L. . In some embodiments, the dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of these comprises one or more BTK inhibitor resistance mutations. Non-limiting examples of BTK inhibitor resistance mutations are described in Tables 2 and 3. In some embodiments, the BTK resistance mutation is a mutation at amino acid 481 of BTK. In some embodiments, the BTK inhibitor resistance mutation is C481S. In some embodiments, the BTK inhibitor resistance mutation is C481F. In some embodiments, the BTK inhibitor resistance mutation is T474I. In some embodiments, the BTK inhibitor resistance mutation is a mutation in PLCγ2 (e.g., a mutation at amino acid positions 244, 257, 334, 495, 664, 665, 707, 708, 742, 845, 848, 993, 1140 or 1141. )to be. In some embodiments, the dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of these is the result of one or more mutations in the one or more BCR signaling pathway proteins. In some embodiments, the BCR signaling pathway protein is selected from the group consisting of Cyclin-D1, CARD11, CD79B, CD79A, MYD88, and combinations thereof. In some embodiments, cancers with dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of these are determined using regulatory agency-approved, e.g., FDA-approved assays or kits. In some embodiments, a tumor that is positive for dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of these is a tumor that is positive for one or more BTK inhibitor resistance mutations. In some embodiments, tumors with dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of these are determined using regulatory agency-approved, e.g., FDA-approved assays or kits.

In some embodiments of any of the methods or uses described herein, the subject is a tumor in which the subject has a dysregulation of the expression or activity or level of a BTK gene, a BTK kinase, or any of them (e.g., one or more BTK inhibitors Tumors with resistant mutations). In some embodiments, the clinical record indicates that the subject should be treated with a compound of Formula I as provided herein, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. . In some embodiments, the cancer having dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of these is a cancer having one or more BTK inhibitor resistance mutations. In some embodiments, cancers with dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of these are determined using regulatory agency-approved, e.g., FDA-approved assays or kits. In some embodiments, a tumor that is positive for dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of these is a tumor that is positive for one or more BTK inhibitor resistance mutations. In some embodiments, tumors with dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of these are determined using regulatory agency-approved, e.g., FDA-approved assays or kits.

A therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, amorphous or polyvalent, to a subject having a clinical record indicating that the subject has a dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of them. Also provided is a method of treating a subject comprising administering the form, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. A compound of formula I for the manufacture of a medicament for the treatment of BTK-associated cancer in a subject having a clinical record indicating that the subject has dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of these, or Also provided is the use of a pharmaceutically acceptable salt, amorphous or polymorphic form thereof or a spray-dried dispersion thereof. Some embodiments of these methods and uses perform assays (e.g., in vitro assays) on samples obtained from the subject so that the subject is dysregulated in the expression or activity or level of the BTK gene, BTK kinase, or any of these. Determining whether or not to have, and information that the subject has been identified as having a dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of them, in the subject's clinical file (e.g., a computer-readable medium ) May further include the step of recording. In some embodiments, the assay is an in vitro assay. For example, the assay uses next-generation sequencing, immunohistochemistry, immunoblot or digested FISH analysis. In some embodiments, the assay is a regulatory agency-approved, e.g., FDA-approved kit. In some embodiments, the assay is a liquid biopsy. In some embodiments, the dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of these comprises one or more BTK inhibitor resistance mutations. In some embodiments, the dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of these is the result of one or more mutations in the one or more BCR signaling pathway proteins. In some embodiments, the BCR signaling pathway protein is selected from the group consisting of Cyclin-D1, CARD11, CD79B, CD79A, MYD88, and combinations thereof. Methods of treating a subject are also provided herein. In some embodiments, the method comprises performing an assay on a sample obtained from the subject to determine whether the subject has dysregulation of the expression or level of the BTK gene, BTK protein, or any of these. In some such embodiments, the method provides a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, amorphous, or a subject determined to have dysregulation of the expression or activity or level of the BTK gene, BTK protein, or any of these. It also includes administering the polymorphic form, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. In some embodiments, the method comprises determining that the subject has dysregulation of the expression or level of the BTK gene, BTK protein, or any of them through an assay performed on a sample obtained from the subject. In such embodiments, the method also comprises administering to the subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. In some embodiments, the dysregulation in the BTK gene, BTK kinase protein, or expression or activity thereof is a gene or chromosomal translocation that causes the expression of a BTK fusion protein (eg, any BTK fusion protein described herein). In some embodiments, the dysregulation in the expression or activity or level of the BTK gene, BTK kinase protein, or any of them is one or more point mutations in the BTK gene (e.g., any one of the BTK point mutations described herein. More than one). One or more point mutations in the BTK gene are, for example, one or more of the following amino acid substitutions: T117P, T316A, T474I, T474M, T474S, C481S, C481F, C481T, C481G, C481R, L528W, P560L, R562W, R562G and F601L. Can induce the translation of BTK protein with. In some embodiments, the dysregulation in the expression or activity or level of the BTK gene, BTK kinase protein, or any of them is one or more BTK inhibitor resistance mutations (e.g., of one or more BTK inhibitor resistance mutations described herein. Any combination). In some embodiments, the dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of these is the result of one or more mutations in the one or more BCR signaling pathway proteins. In some embodiments, the BCR signaling pathway protein is selected from the group consisting of Cyclin-D1, CARD11, CD79B, CD79A, MYD88, and combinations thereof. Some embodiments of these methods further comprise administering to the subject another anticancer agent (eg, a second BTK inhibitor or immunotherapy).

Also provided is a method of selecting a treatment for a subject identified or diagnosed with a BTK-associated cancer (eg, in vitro method). Some embodiments may further comprise administering the selected treatment to a subject identified or diagnosed as having a BTK-associated cancer. For example, the treatment chosen may comprise administration of a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. Some embodiments perform an assay on a sample obtained from a subject to determine whether the subject has a dysregulation of the expression or activity or level of a BTK gene, a BTK kinase, or any of them, and a BTK gene, a BTK kinase. Or it may further include the step of identifying and diagnosing a subject determined to have dysregulation of the expression or activity or level of any of these as having BTK-associated cancer. In some embodiments, the dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of these is the result of one or more mutations in the one or more BCR signaling pathway proteins. In some embodiments, the BCR signaling pathway protein is selected from the group consisting of Cyclin-D1, CARD11, CD79B, CD79A, MYD88, and combinations thereof. In some embodiments, the cancer is a BTK-associated cancer with one or more BTK inhibitor resistance mutations. In some embodiments, the subject is a regulatory agency-approved, e.g., FDA-approved, for identifying dysregulation of the expression or activity or level of a BTK gene, BTK kinase, or any of these in a subject or a biopsy sample from a subject. Has been identified or diagnosed as having BTK-associated cancer through the use of the kit. In some embodiments, the BTK-associated cancer is a cancer described herein or known in the art. In some embodiments, the assay is an in vitro assay. For example, the assay uses next-generation sequencing, immunohistochemistry, immunoblot or digested FISH analysis. In some embodiments, the assay is a regulatory agency-approved, e.g., FDA-approved kit. In some embodiments, the assay is a liquid biopsy.

Perform an assay on a sample obtained from a subject to determine whether the subject has a dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of them (e.g., one or more BTK inhibitor resistance mutations). And identifying or diagnosing a subject determined to have dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of them as having BTK-associated cancer. Methods of selection are also provided herein. Some embodiments further comprise administering the selected treatment to a subject identified or diagnosed with a BTK-associated cancer. For example, the selected treatment is a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof for a subject identified or diagnosed as having BTK-associated cancer, or Administration of a pharmaceutical composition thereof. In some embodiments, the assay is an in vitro assay. For example, the assay uses next-generation sequencing, immunohistochemistry, immunoblot or digested FISH analysis. In some embodiments, the assay is a regulatory agency-approved, e.g., FDA-approved kit. In some embodiments, the assay is a liquid biopsy.

Selecting, identifying or diagnosing a subject with BTK-associated cancer, and a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical thereof Also provided is a method of selecting a subject for treatment, comprising selecting a subject for treatment including administration of the composition. In some embodiments, identifying or diagnosing a subject as having a BTK-associated cancer involves performing an assay on a sample obtained from the subject so that the subject modulates the expression or activity or level of the BTK gene, BTK kinase, or any of these. Determining whether to have an abnormality, and identifying or diagnosing a subject determined to have dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of them as having BTK-associated cancer. I can. In some embodiments, the method of selecting a subject for treatment can be used as part of a clinical study involving administration of various treatments of BTK-associated cancer. In some embodiments, the BTK-associated cancer is a cancer having one or more BTK inhibitor resistance mutations. In some embodiments, the assay is an in vitro assay. For example, the assay uses next-generation sequencing, immunohistochemistry or digestive FISH analysis. In some embodiments, the assay is a regulatory agency-approved, e.g., FDA-approved kit. In some embodiments, the assay is a liquid biopsy. In some embodiments, the dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of these comprises one or more BTK inhibitor resistance mutations. In some embodiments, the dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of these is the result of one or more mutations in the one or more BCR signaling pathway proteins. In some embodiments, the BCR signaling pathway protein is selected from the group consisting of Cyclin-D1, CARD11, CD79B, CD79A, MYD88, and combinations thereof.

a) dysregulation of the expression or activity or level of a BCR signaling pathway gene, BCR signaling pathway protein, or any one of them in a sample from a subject in need of treatment for cancer (e.g., BTK-associated cancer) Detecting a; And b) administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. For example, methods of treating BTK-associated cancer) are also provided herein. Some embodiments of these methods perform an assay (e.g., an in vitro assay) on a sample obtained from a subject so that the subject can express or activate a BCR signaling pathway gene, a BCR signaling pathway protein, or either Or determining whether to have a level of dysregulation, and information that the subject has been found to have a BCR signaling pathway gene, a BCR signaling pathway protein, or any one of these expressions or activities or levels of dysregulation. And writing to a clinical file (eg, a computer readable medium). In some embodiments, the assay is an in vitro assay. For example, the assay uses next-generation sequencing, immunohistochemistry, immunoblot or digested FISH analysis. In some embodiments, the assay is a regulatory agency-approved, e.g., FDA-approved kit. In some embodiments, the BCR signaling pathway protein is selected from the group consisting of Cyclin-D1, CARD11, CD79B, CD79A, MYD88, and combinations thereof.

A therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable amount thereof to a subject having a clinical record indicating that the subject has dysregulation of the expression or activity or level of the BCR signaling pathway gene, BCR signaling pathway protein, or any of these. Also provided is a method of treating a subject comprising administering a salt, amorphous or polymorphic form, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. Some embodiments of these methods perform an assay (e.g., an in vitro assay) on a sample obtained from a subject so that the subject can express or activate a BCR signaling pathway gene, a BCR signaling pathway protein, or either Or determining whether to have a level of dysregulation, and information that the subject has been found to have a BCR signaling pathway gene, a BCR signaling pathway protein, or any one of these expressions or activities or levels of dysregulation. And writing to a clinical file (eg, a computer readable medium). In some embodiments, the assay is an in vitro assay. For example, the assay uses next-generation sequencing, immunohistochemistry, immunoblot or digested FISH analysis. In some embodiments, the assay is a regulatory agency-approved, e.g., FDA-approved kit. In some embodiments, the BCR signaling pathway protein is selected from the group consisting of Cyclin-D1, CARD11, CD79B, CD79A, MYD88, and combinations thereof.

In some embodiments of any of the methods or uses described herein, a sample from a subject is used to determine whether the subject has dysregulation of the expression or activity or level of a BTK gene or BTK kinase, or any of them. Assays include, for example, next-generation sequencing, immunohistochemistry, fluorescence microscopy, digestive FISH analysis, Southern blotting, Western blotting, FACS (fluorescence-activated cell sorting) analysis, Northern blotting and PCR-based amplification (e.g. For example, RT-PCR (reverse transcriptase-polymerase chain reaction) and quantitative real-time RT-PCR). As is well known in the art, assays are typically performed using, for example, at least one labeled nucleic acid probe or at least one labeled antibody or antigen-binding fragment thereof. Assays can use other detection methods known in the art to detect dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of them (see, e.g., references cited herein. ). In some embodiments, the dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of these comprises one or more BTK inhibitor resistance mutations. In some embodiments, the sample is a biological sample or a biopsy sample (eg, a paraffin-embedded biopsy sample) from a subject. In some embodiments, the subject is a subject suspected of having a BTK-associated cancer, a subject having one or more symptoms of BTK-associated cancer, and/or a subject having an increased risk of developing BTK-associated cancer.

In some embodiments, dysregulation of the expression or activity or level of a BTK gene, BTK kinase, or any of these can be identified using a liquid biopsy (variously referred to as a fluid biopsy or a fluid phase biopsy). See, for example, Karachialiou et al., "Real-time liquid biopsies become a reality in cancer treatment", Ann. Transl. Med., 3(3):36, 2016]. Liquid biopsy methods can be used to detect total tumor burden and/or dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of these. Liquid biopsies can be performed on biological samples obtained relatively easily (eg, through simple blood collection) from a subject. In some embodiments, a liquid biopsy can be used to detect the presence of a dysregulation of the expression or activity or level of a BTK gene, BTK kinase, or any of these, at an earlier stage than traditional methods. In some embodiments, a biological sample to be used for a liquid biopsy may include blood, plasma, urine, cerebrospinal fluid, saliva, sputum, broncho-alveolar lavage fluid, bile, lymph fluid, cyst, feces, ascites, and combinations thereof. In some embodiments, liquid biopsies can be used to detect circulating tumor cells (CTCs). In some embodiments, liquid biopsies can be used to detect cell-free DNA. In some embodiments, the cell-free DNA detected using a liquid biopsy is circulating tumor DNA (ctDNA) derived from tumor cells. Analysis of ctDNA (e.g., using sensitive detection techniques such as, but not limited to, next-generation sequencing (NGS), traditional PCR, digital PCR, or microarray analysis) can be used to determine the expression or activity of the BTK gene, BTK kinase, or any of these. Or it can be used to identify levels of dysregulation.

In some embodiments, ctDNA derived from a single gene can be detected using a liquid biopsy. In some embodiments, a plurality of genes (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60 , 65, 70, 75, 80, 85, 90, 95, 100 or more or any number of genes in between) can be detected using a liquid biopsy. In some embodiments, ctDNAs derived from a plurality of genes are used to detect dysregulation of the expression or activity or level of any of a variety of commercially available test panels (e.g., BTK genes, BTK kinases, or any of them. Designed commercially available test panels). Liquid biopsies include, but are not limited to, dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of them, such as, but not limited to, point mutations or single nucleotide variants (SNV), copy number variants (CNV), gene fusions ( For example, translocations or rearrangements), insertions, deletions or any combination thereof. In some embodiments, liquid biopsies can be used to detect germline mutations. In some embodiments, liquid biopsies can be used to detect somatic mutations. In some embodiments, a liquid biopsy can be used to detect a primary gene mutation (eg, a primary mutation or primary fusion associated with the early occurrence of a disease, eg, cancer). In some embodiments, a liquid biopsy can be used to detect a gene mutation that occurs after the occurrence of a primary gene mutation (eg, a resistance mutation that occurs in response to a treatment administered to a subject). In some embodiments, the dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of these identified using a liquid biopsy is also present in cancer cells (e.g., tumors) present in the subject. In some embodiments, any type of dysregulation of the expression or activity or level of a BTK gene, BTK kinase, or any of these described herein can be detected using a liquid biopsy. In some embodiments, genetic mutations identified via liquid biopsy can be used to identify a subject as a candidate for a particular treatment. For example, detection of a dysregulation of the expression or activity or level of a BTK gene, BTK kinase, or any of these in a subject, may result in the subject being a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, spray- It may indicate that it will be responsive to treatment comprising administration of the dried dispersion or pharmaceutical composition thereof.

Liquid biopsy is a diagnostic process, monitoring process, and/or course of treatment to determine one or more clinically significant parameters, including, but not limited to, disease progression, efficacy of treatment, or development of resistant mutations after administration of treatment to a subject. Can be performed multiple times during. For example, during the diagnosis process, the monitoring process and/or the treatment process, a first liquid biopsy may be performed at a first time point, and a second liquid biopsy may be performed at a second time point. In some embodiments, the first time point may be a time point before diagnosis of the subject as having a disease (e.g., when the subject is healthy), and the second time point may be a time point after the occurrence of the disease in the subject (e.g. For example, the second time point can be used to diagnose a subject having a disease). In some embodiments, the first time point can be a time point before diagnosing the subject as having the disease (e.g., when the subject is healthy), after which the subject is monitored, and the second time point is after monitoring the subject. It could be a point in time. In some embodiments, the first time point can be a time point after diagnosing the subject as having the disease, after which treatment is administered to the subject, and the second time point can be a time point after the treatment is administered; In this case, the second time point can be used to evaluate the efficacy of the treatment (e.g., if the gene mutation(s) detected at the first time point is abundantly reduced or not detectable) or that has occurred as a result of treatment. It can be used to determine the presence of resistant mutations. In some embodiments, the treatment to be administered to a subject may comprise a compound of Formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof.

In some embodiments, the efficacy of a compound of Formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof, is obtained from a subject at different time points. It can be determined by evaluating the allele frequency of dysregulation of the BTK gene in the cfDNA obtained from the subject at time 1 and the cfDNA obtained from the subject at the second time point, wherein the compound of formula I or a pharmaceutically acceptable salt thereof, amorphous or At least one dose of the polymorphic form, a spray-dried dispersion thereof, or a pharmaceutical composition thereof is administered to the subject between the first and second time points. Some embodiments of these methods give the subject at least one of a compound of formula (I) or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof between the first time point and the second time point. It may further comprise the step of administering multiple doses. For example, compared to the allele frequency of dysregulation of BTK gene in cfDNA obtained from the subject at the first time point (AF) compared to the allele frequency of dysregulation of BTK gene in cfDNA obtained from the subject at the second time point (AF ) Of decrease (e.g., 1% to about 99% decrease, 1% to about 95% decrease, 1% to about 90% decrease, 1% to about 85% decrease, 1% to about 80% decrease, 1% To about 75% decrease, 1% decrease to about 70% decrease, 1% decrease to about 65% decrease, 1% decrease to about 60% decrease, 1% decrease to about 55% decrease, 1% decrease to about 50% decrease , 1% reduction to about 45% reduction, 1% reduction to about 40% reduction, 1% reduction to about 35% reduction, 1% reduction to about 30% reduction, 1% reduction to about 25% reduction, 1% reduction to About 20% decrease, 1% decrease to about 15% decrease, 1% decrease to about 10% decrease, 1% to about 5% decrease, about 5% to about 99% decrease, about 10% to about 99% decrease, about 15% to about 99% reduction, about 20% to about 99% reduction, about 25% to about 99% reduction, about 30% to about 99% reduction, about 35% to about 99% reduction, about 40% to about 99 % Reduction, about 45% to about 99% reduction, about 50% to about 99% reduction, about 55% to about 99% reduction, about 60% to about 99% reduction, about 65% to about 99% reduction, about 70 % To about 99% reduction, about 75% to about 95% reduction, about 80% to about 99% reduction, about 90% reduction to about 99% reduction, about 95% to about 99% reduction, about 5% to about 10 % Reduction, about 5% to about 25% reduction, about 10% to about 30% reduction, about 20% to about 40% reduction, about 25% to about 50% reduction, about 35% to about 55% reduction, about 40 % To about 60% reduction, about 50% reduction to about 75% reduction, about 60% reduction To about 80% reduction, or about 65% to about 85% reduction), the compound of formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form, spray-dried dispersion thereof, or a pharmaceutical composition thereof is effective in a subject. Indicates that. Alternatively, the allele frequency of dysregulation of the BTK gene in the cfDNA obtained from the subject at the second time point compared to the allele frequency (AF) of the dysregulation of the BTK gene in the cfDNA obtained from the subject at the first time point (AF ) Indicates that the compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical composition thereof is not effective in the subject (e.g., the subject has the formula I Or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof). Some embodiments of these methods further comprise administering to the subject an additional dose of a compound of Formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. Wherein the compound of formula (I) or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical composition thereof is determined to be effective. Some embodiments of these methods provide a different treatment (e.g., to a subject determined to be ineffective in a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form, spray-dried dispersion thereof, or pharmaceutical composition thereof). , Treatment that does not include administration in the form of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof as monotherapy).

In some examples of these methods, the time difference between the first time point and the second time point is about 1 day to about 1 year, about 1 day to about 11 months, about 1 day to about 10 months, about 1 day to about 9 months. , About 1 day to about 8 months, about 1 day to about 7 months, about 1 day to about 6 months, about 1 day to about 5 months, about 1 day to about 4 months, about 1 day to about 3 months, about 1 day to about 10 weeks, about 1 day to about 2 months, about 1 day to about 6 weeks, about 1 day to about 1 month, about 1 day to about 25 days, about 1 day to about 20 days, about 1 day To about 15 days, about 1 to about 10 days, about 1 to about 5 days, about 2 to about 1 year, about 5 to about 1 year, about 10 to about 1 year, about 15 days to about 1 year, about 20 days to about 1 year, about 25 days to about 1 year, about 1 month to about 1 year, about 6 weeks to about 1 year, about 2 months to about 1 year, about 3 months to about 1 year , About 4 months to about 1 year, about 5 months to about 1 year, about 6 months to about 1 year, about 7 months to about 1 year, about 8 months to about 1 year, about 9 months to about 1 year, about 10 months to about 1 year, about 11 months to about 1 year, about 1 day to about 7 days, about 1 day to about 14 days, about 5 days to about 10 days, about 5 days to about 20 days, about 10 days To about 20 days, about 15 days to about 1 month, about 15 days to about 2 months, about 1 week to about 1 month, about 2 weeks to about 1 month, about 1 month to about 3 months, about 3 months to about 6 months, about 4 months to about 6 months, about 5 months to about 8 months, or about 7 months to about 9 months. In some embodiments of these methods, the subject can be identified as having a cancer that previously had a dysregulated BTK gene (eg, any example of a dysregulated BTK gene described herein). In some embodiments of these methods, the subject may have previously been diagnosed as having any type of cancer described herein. In some embodiments of these methods, the subject may have one or more metastases (eg, one or more bone metastases).

In some of the above embodiments, cfDNA comprises ctDNA, such as BTK-associated ctDNA. For example, cfDNA is ctDNA, such as BTK-associated ctDNA. In some embodiments, at least a portion of the cfDNA is determined to be a BTK-associated ctDNA, e.g., a sequenced and/or quantified amount of total cfDNA is determined to have a BTK fusion and/or a BTK resistance mutation.

In the field of medical oncology, it is common practice to use a combination of different types of treatment to treat each cancer subject. In medical oncology, in addition to the compositions provided herein, other component(s) of such combination therapy or therapy may be, for example, surgery, radiotherapy and chemotherapeutic agents such as other kinase inhibitors, signal transduction inhibitors and/or monoclonal It can be an antibody. For example, the surgery may be an open surgery or minimally invasive surgery. Thus, the compounds of formula I, or pharmaceutically acceptable salts, amorphous or polymorphic forms thereof, may also be useful as adjuvants for cancer treatment, i.e. they are one or more additional therapies or therapeutic agents, for example the same or It can be used in combination with chemotherapeutic agents that act by different mechanisms of action. In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof may be used prior to administration of the additional therapeutic agent or additional therapy. For example, a subject in need thereof is administered one or more doses of a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form, a spray-dispersion thereof, or a pharmaceutical composition thereof for a predetermined period of time, and then, At least partial resection of the tumor can be performed. In some embodiments, treatment with one or more doses of a compound of Formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dispersion thereof, or a pharmaceutical composition thereof, the size of the tumor prior to at least partial resection of the tumor. (E.g., tumor burden) is reduced.

In some embodiments of any of the methods described herein, the compound of formula (I), or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dispersion thereof, or a pharmaceutical composition thereof is one or more additional therapies or therapeutic agents (e.g. For example, chemotherapeutic agents) are administered in combination with a therapeutically effective amount of at least one additional therapeutic agent.

Non-limiting examples of additional therapeutic agents include other BTK-targeting therapeutics (i.e., first or second BTK kinase inhibitors), other kinase-targeting therapeutics (e.g., JAK, Src or IRAK family kinase-targeting therapeutics such as JAK1, JAK2, JAK3, TYK2, IRAK1, IRAK4, Src, Yes, Fyn, Fgr, Lck, Hck, Blk, Lyn, or Frk inhibitors), signaling pathway inhibitors, checkpoint inhibitors, modulators of the apoptosis pathway (e.g. Obatoclock Su); Other protein inhibitors (eg, anti-apoptotic protein inhibitors, heat shock protein inhibitors, nuclear efflux protein inhibitors, histone deacetylase inhibitors, E3 ubiquitin ligase inhibitors, or histone-lysine N-methyltransferase inhibitors); Cytotoxic chemotherapeutic agents, angiogenesis-targeting therapy, immune-targeting agents including immunotherapy, and radiotherapy.

In some embodiments, the other BTK-targeting therapeutic agent is a multikinase inhibitor that exhibits BTK inhibitory activity. In some embodiments, other BTK-targeted treatment inhibitors are selective for BTK kinases. Exemplary BTK kinase inhibitors are less than about 1000 nM, less than about 500 nM, less than about 200 nM, less than about 100 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM, as measured in an assay as described herein. Or less than about 1 nM of BTK kinase inhibitory activity (IC ₅₀ ). _{In some embodiments, the BTK kinase inhibitor has an inhibitory activity against BTK kinase (IC 50} ) of less than about 25 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM, as measured in an assay as provided herein. Can be indicated.

Non-limiting examples of BTK-targeted therapeutic agents (e.g., a first BTK inhibitor or a second BTK inhibitor) include ibrutinib (PCI-32675, Imbruvica®) (1-[(3R)-3- [4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one); AC0058 (AC0058TA); N-(3-((2-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-4- Yl)oxy)phenyl)acrylamide; Acalabrutinib (ACP-196, Calquence®, rINN) (4-[8-amino-3-[(2S)-1-but-2-ylnoylpyrrolidin-2-yl]im Polyzo[1,5-a]pyrazin-1-yl]-N-pyridin-2-ylbenzamide); Janubrutinib (BGB-3111) ((7R)-2-(4-phenoxyphenyl)-7-(1-prop-2-enoylpiperidin-4-yl)-1,5,6, 7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide); Sfebrutinib (AVL-292, 1202757-89-8, Cc-292) (N-[3-[[5-fluoro-2-[4-(2-methoxyethoxy)anilino]pyrimidine- 4-yl]amino]phenyl]prop-2-enamide); Porceltinib (HM71224, LY3337641) (N-[3-[2-[4-(4-methylpiperazin-1-yl)anilino]furo[3,2-d]pyrimidin-4-yl]oxyphenyl ]Prop-2-enamide); Evobrutinib (MSC 2364447, M-2951) (1-[4-[[[6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl]amino]methyl]piperidine-1- Yl]prop-2-en-1-one); Tyrabrutinib (ONO-4059, GS-4059, ONO/GS-4059, ONO-WG-307) (1-[4-[[[6-amino-5-(4-phenoxyphenyl)pyrimidine-4 -Yl]amino]methyl]piperidin-1-yl]prop-2-en-1-one); Becabrutinib (SNS-062) ((3R,4S)-1-(6-amino-5-fluoropyrimidin-4-yl)-3-[(3R)-3-[3-chloro-5- (Trifluoromethyl)anilino]-2-oxopiperidin-1-yl]piperidine-4-carboxamide); Dasatinib (Sprycel®; BMS-354825) (N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)piperazin-1-yl ]-2-methylpyrimidin-4-yl]amino]-1,3-thiazole-5-carboxamide); PRN1008, PRN473, ABBV-105, CG'806, ARQ 531, BIIB068, AS871, CB1763, CB988, GDC-0853, RN486, GNE-504, GNE-309, BTK Max, CT-1530, CGI-1746, CGI- 560, LFM A13, TP-0158, dtrmwxhs-12, CNX-774, and LOU064. BTK inhibitors can be covalent inhibitors (eg, compounds that bind to C481 of BTK) or non-covalent inhibitors. Exemplary covalent inhibitors of BTK kinase include Ibrutinib, PRN1008, PRN473, ABBV-105, AC0058, Acalabrutinib, Janubrutinib, Sfebrutinib, Foceltinib, Evobrutinib, M7583 and Tirablutinib. However, it is not limited thereto. Exemplary non-covalent inhibitors of BTK kinase include, but are not limited to, CG'806, ARQ 531, BIIB068, Becabrutinib, AS871, CB1763, CB988, GDC-0853, RN486 and Dasatinib.

Further examples of other BTK kinase inhibitors are described, for example, in US Pat. Nos. 9,150,517; 9,149,464, 10,023,534; 10,005,784; 9,994,576; 9,951,056; 9,944,622; 9,926,299; 9,920,031; And 9,908,872; US Publication No. 2018/0194762; 2018/0194739; 2018/0186780; 2018/0179210; 2018/0162861; 2018/0141962; 2018/0134719; 2018/0127411; 2018/0118766; 2018/0093973; 2018/0085372; 2018/0079758; 2018/0057500; 2018/0055846; 2018/0051024; 2018/0051036; 2018/0037583; 2018/0030037; And 2018/0030027; And International Publication No. WO 2014/075035; 2018/130213; 2018/113085; 2017/134685; 2018/103060; 2018/095398; 2018/092047; 2018/088780; 2018/035080; 2018/035072; 2018/032104; And 2018/022911, all of which are incorporated herein by reference.

In some embodiments, the additional therapeutic agent is an inhibitor of a protein upstream of BTK in the BCR signaling pathway, such as Syk, Lyn, BCR, PI3K, CD19 or BCAP.

In some embodiments, the additional therapeutic agent is a protein downstream of BTK in the BCR signaling pathway, e.g. PLCγ2, SOS, Ras, c-Raf, MEK1, MEK2, Erk1, Erk2, PKC, MALT1, IKK, NF-κB or It is an inhibitor of _{IP 3 R.}

Non-limiting examples of targeted therapies of the JAK family (e.g., JAK1, JAK2, JAK3 and TYK2) include tofacitinib, luxolitinib, oklacitinib, varicitinib (OLUMIANT®; LY-3009104 , INCB-28050), Pilgotinib (G-146034, GLPG-0634), Gandotinib (LY-2784544), Restaurtinib (CEP-701), Momellotinib (GS-0387, CYT-387), Park Litinib (SB1518), PF-04965842, upadacitinib (ABT-494), pepicitinib (ASP015K, JNJ-54781532) and pedratinib (SAR302503). Additional JAK family targeted therapeutics include U.S. Patent Nos. 8,604,043, 7,834,022, 8,486,902, 8,530,485, 7,598,257, 8,541,425, 8,410,265, 9,987,276 and 9,949,971, and U.S. Patent Application Publication Nos. 2018/0051036 A1, 2010/0298355 A1, 2008/0312258 A1, 2011 /0082159 A1, 2011/0086810 A1, 2013/0345157 A1, 2014/0018374 A1, 2014/0005210 A1, 2011/0223210 A1, 2011/0224157 A1, 2007/0135461 A1, 2010/0022522 A1, 2013/0253193 A1, 2013 /0253191 A1, 2013/0253190 A1, 2010/0190981 A1, 2013/0338134 A1, 2008/0312259 A1, 2014/0094477 A1 and 2014/0094476 A1, the disclosures of which are incorporated herein by reference .

Src, family (Src, Yes, Fyn, Fgr, Lck, Hck, Blk, Lyn or Frk) Non-limiting examples of targeted therapeutics include Dasatinib (Spricel®), INNO-406, LCB03-0110, KX2-391, Bosutinib, saracatinib, PP1, PP2 and quercetin. Additional Src family targeted therapeutics include P.C.T. And those described in Publication Nos. WO 2018/049127, WO 2018/035072 and WO 2007/026720.

Non-limiting examples of IRAK (IRAK1, IRAK2, IRAK3 or IRAK4) family inhibitors include ND-2158 and ND-2110. Additional IRAK family targeted therapeutics include U.S. Patent Nos. 9,982,000, 9,969,749, 9,969,710, 9,890,145, 9,862,715, 9,815,836, 9,790,234, 9,732,095 and 9,617,282, and U.S. Patent Application Publication Nos. 2017/0035881 and P.C.T. Includes those described in Publication Nos. WO 2016/174183 and WO 2017/205769, all of which are incorporated herein by reference.

In some embodiments, the kinase inhibitor is PI3K, JAK1, JAK2, JAK3, TYK2, IRAK1, IRAK2, IRAK3, IRAK4, BMX, TAK1, Src, Yes, Fyn, Fgr, Lck, Hck, Blk, Lyn, Frk, PIM, Inhibits a kinase selected from the group consisting of mTOR, ROR-1, Syk, PKC, and combinations thereof.

Non-limiting examples of receptor tyrosine kinase (e.g., Trk) targeted therapeutics include afatinib, cabozantinib, cetuximab, crizotinib, dabrafenib, entrectinib, erlotinib, gefitinib, imatinib , Lapatinib, Restaurtinib, Nilotinib, Pazopanib, Panitumumab, Pertuzumab, Sunitinib, Trastuzumab, 1-((3S,4R)-4-(3-fluorophenyl)- 1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(2-methylpyrimidin-5-yl)-1-phenyl-1H-pyrazole-5- Japan) Urea, AG 879, AR-772, AR-786, AR-256, AR-618, AZ-23, AZ623, DS-6051, Goe 6976, GNF-5837, GTx-186, GW 441756, Roxo-101 , MGCD516, PLX7486, RXDX101, VM-902A, TPX-0005, and TSR-011. Additional Trk targeted therapeutics are described in US Pat. Nos. 8,450,322; 8,513,263; 8,933,084; 8,791,123; 8,946,226; 8,450,322; 8,299,057; And 8,912,194; US Publication No. 2016/0137654; 2015/0166564; 2015/0051222; 2015/0283132; And 2015/0306086; International Publication No. WO 2010/033941; WO 2010/048314; WO 2016/077841; WO 2011/146336; WO 2011/006074; WO 2010/033941; WO 2012/158413; WO 2014078454; WO 2014078417; WO 2014078408; WO 2014078378; WO 2014078372; WO 2014078331; WO 2014078328; WO 2014078325; WO 2014078323; WO 2014078322; WO 2015175788; WO 2009/013126; WO 2013/174876; WO 2015/124697; WO 2010/058006; WO 2015/017533; WO 2015/112806; WO 2013/183578; And WO 2013/074518, all of which are incorporated herein by reference in their entirety.

Further examples of Trk inhibitors are U.S. Patent No. 8,637,516, International Publication No. WO 2012/034091, U.S. Patent No. 9,102,671, International Publication No. WO 2012/116217, U.S. Publication No. 2010/0297115, International Publication No. WO 2009/053442, U.S. Patent 8,642,035, International Publication No. WO 2009092049, US Patent No. 8,691,221, International Publication No. WO2006131952, all of which are incorporated herein by reference in their entirety. Exemplary Trk inhibitors are described in Cancer Chemother. Pharmacol. 75(1):131-141, 2015]; And in ACS Med. Chem. Lett. 3(2):140-145, 2012] described in GNF-5837 (N-[3-[[2,3-dihydro-2-oxo-3-(1H-pyrrol-2-ylmethylene)-1H- Indole-6-yl]amino]-4-methylphenyl]-N'-[2-fluoro-5-(trifluoromethyl)phenyl]-urea), each of which is incorporated herein by reference in its entirety. Included as.

Additional examples of Trk inhibitors include those disclosed in US Publication No. 2010/0152219, US Patent No. 8,114,989 and International Publication No. WO 2006/123113, all of which are incorporated herein by reference in their entirety. Exemplary Trk inhibitors include AZ623, described in Cancer 117(6):1321-1391, 2011; See Cancer Biol. Ther. 16(3):477-483, 2015]; See Cancer Chemother. Pharmacol. 70:477-486, 2012; See Mol. Cancer Ther. 8:1818-1827, 2009] AZ-23 ((S)-5-chloro-N2-(1-(5-fluoropyridin-2-yl)ethyl)-N4-(5-isopropoxy- 1H-pyrazol-3-yl)pyrimidine-2,4-diamine); And AZD7451, each of which is incorporated by reference in its entirety.

Trk inhibitors are described in US Pat. Nos. 7,615,383; 7,384,632; 6,153,189; 6,027,927; 6,025,166; 5,910,574; 5,877,016; And 5,844,092, each of which is incorporated by reference in its entirety.

Further examples of Trk inhibitors are described in Int. J. Cancer 72:672-679, 1997]; Acta Derm. Venereol. 95:542-548, 2015] as described in CT327; The compounds described in International Publication No. WO 2012/034095; The compounds described in US Pat. No. 8,673,347 and International Publication No. WO 2007/022999; The compounds described in U.S. Patent No. 8,338,417; The compounds described in International Publication No. WO 2016/027754; The compounds described in U.S. Patent No. 9,242,977; The compounds described in US Publication No. 2016/0000783; Sunitinib (N-(2-diethylaminoethyl)-5-[(Z)-(5-fluoro-2-oxo-1H-indole- as described in PLOS One 9:e95628, 2014] 3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide); The compounds described in International Publication No. WO 2011/133637; The compounds described in U.S. Patent No. 8,637,256; See Expert. Opin. Ther. Pat. 24(7):731-744, 2014]; See Expert Opin. Ther. Pat. 19(3):305-319, 2009]; (R)-2-phenylpyrrolidine substituted imidazopyridazine, eg ACS Med. Chem. Lett. 6(5):562-567, 2015] GNF-8625, (R)-1-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imide Dazo[1,2-b]pyridazin-3-yl)-[2,4'-bipyridin]-2'-yl)piperidin-4-ol; GTx-186, etc. as described in PloS One 8(12):e83380, 2013; See Mol. Cell Biochem. 339(1-2):201-213, 2010] K252a ((9S-(9α,10β,12α))-2,3,9,10,11,12-hexahydro-10-hydroxy -10-(methoxycarbonyl)-9-methyl-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3, 4-i][1,6]benzodiazosin-1-one); 4-aminopyrazolylpyrimidines, eg J. Med. Chem. 51(15):4672-4684, 2008] AZ-23 (((S)-5-chloro-N2-(1-(5-fluoropyridin-2-yl)ethyl)-N4-( 5-isopropoxy-1H-pyrazol-3-yl)pyrimidine-2,4-diamine)); See Mol. Cancer Ther. 6:3158, 2007] PHA-739358 (Danusertip) as described; Literature [J. Neurochem. 72:919-924, 1999] as described in Goe 6976 (5,6,7,13-tetrahydro-13-methyl-5-oxo-12H-indolo[2,3-a]pyrrolo[3, 4-c]carbazole-12-propanenitrile); GW441756 ((3Z)-3-[(1-methylindol-3-yl)methylidene]-1H-pyrrolo[3,2-b]pyridin-2 as described in IJAE 115:117, 2010 -On); Literature [J. Carcinog. 12:22, 2013] Milsiclip (PHA-848125AC); AG-879 ((2E)-3-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2-cyano-2-propenthioamide); Altiratinib (N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-N-(4-fluorophenyl)cyclo Propane-1,1-dicarboxamide); Carbozantinib (N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide) ; Restaurtinib ((5S,6S,8R)-6-hydroxy-6-(hydroxymethyl)-5-methyl-7,8,14,15-tetrahydro-5H-16-oxa-4b,8a, 14-triaza-5,8-methanodibenzo[b,h]cycloocta[jkl]cyclopenta[e]-as-indacene-13(6H)-one); Dobatinib (4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one mono 2 -Hydroxypropanoate hydrate); Citrabatinib (N-(3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]) Pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide); ONO-5390556; Regorafenib (4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridin-2-carboxy Amide hydrate); And VSR-902A; All of the above references are incorporated herein by reference in their entirety.

The ability of a Trk inhibitor to act as a TrkA, TrkB and/or Trk C inhibitor can be tested using the assays described in Examples A and B of US Pat. No. 8,513,263, which is incorporated herein by reference.

In some embodiments, the receptor tyrosine kinase inhibitor is an epidermal growth factor receptor tyrosine kinase family inhibitor (EGFR). For example, EGFR family inhibitors are osimertinib (AZD9291, Merrelectinib, TAGRISSO ^TM ), Erlotinib (TARCEVA®), Gefitinib (IRESSA®), Cetuk Simab (ERBITUX®), Necitumumab (PORTRAZZA ^TM , IMC-11F8), neratinib (HKI-272, NERLYNX®), lapatinib (TYKERB )®), panitumumab (ABX-EGF, VECTIBIX®), vandetanib (CAPRELSA®), rosiletinib (CO-1686), olmutinib (OLITA ^TM , HM61713, BI-1482694), Nakuotinib (ASP8273), Nazartinib (EGF816, NVS-816), PF-06747775, Icontinib (BPI-2009H), Afatinib (BIBW 2992, GILOTRIF) ®), Dacomitinib (PF-00299804, PF-804, PF-299, PF-299804), Abitinib (AC0010), AC0010MA EAI045, Matuzumab (EMD-7200), Nimotuzumab (h-R3, BIOMAb EGFR®), zalutumab, MDX447, depatuxizumab (humanized mAb 806, ABT-806), depatuxizumab mapodotin (ABT-414), ABT-806, mAb 806, canertinib (CI- 1033), Shikonin, Shikonin derivatives (e.g., deoxyschkonin, isobutyrylschkonin, acetylschkonin, β,β-dimethylacrylschkonin and acetylalkanine), pogiotinib (NOV120101, HM781- 36B), AV-412, Ibrutinib, WZ4002, Brigatinib (AP26113, ALUNBRIG®), Felitinib (EKB-569), Tarloxotinib (TH-4000, PR610), BPI-15086 , Hemay022, ZN-e4, Tessebatinib (KD019, XL647), YH25448, Efitinib (HMPL-813), CK-101, MM-151, AZD3759, ZD6474, PF-0 6459988, barlitinib (ASLAN001, ARRY-334543), AP32788, HLX07, D-0316, AEE788, HS-10296, abitinib, GW572016, pyrotinib (SHR1258), SCT200, CPGJ602, Sym004, MAb-425, Modo Tuximab (TAB-H49), Putuximab (992 DS), Zalutumumab, KL-140, RO5083945, IMGN289, JNJ-61186372, LY3164530, Sym013, AMG 595, AZD8931, AST1306, CP724714, CUDC101, TAK285, Trastuzumab (HERCEPTIN®), Pertuzumab (PERJETA®), Trastuzumab-dkst (OGIVRI®), DXL-702, E-75, PX-104.1, ZW25, Irbinitinib (ARRY-380, ONT-380), TAS0728, Perlinitinib (EKB-569), PKI-166, D-69491, HKI-357, AC-480 (BMS-599626), RB- 200h, Emodin, IDM-1, ado-trastzumab emtansine (KADCYLA®), Gemab, DS-8201a, T-DM1. In some embodiments, the EGFR family inhibitor is osimertinib. In some embodiments, the dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of these comprises expression of BTK-C. In some embodiments, BTK-C is expressed in prostate cancer or breast cancer.

In some embodiments, the signal transduction pathway inhibitor is a Ras-Raf-MEK-ERK pathway inhibitor (e.g., vinimetinib, celumetinib, encorafenib, sorafenib, trametinib and vemurafenib), PI3K- Akt-mTOR-S6K pathway inhibitors (e.g. everolimus, rapamycin, perifosine, temsirolimus), and other kinase inhibitors such as varicitinib, brigatinib, capmatinib, danusertip, eve Lutinib, Milsiclip, Quercetin, Regorafenib, Luxsolitinib, Semaksanib, AP32788, BLU285, BLU554, INCB39110, INCB40093, INCB50465, INCB52793, INCB54828, MGCD265, NMS-088, NMS-1286937, PF 477736 (( R)-amino-N-[5,6-dihydro-2-(1-methyl-1H-pyrazol-4-yl)-6-oxo-1Hpyrrolo[4,3,2-ef][2 ,3]benzodiazepin-8-yl]-cyclohexaneacetamide), PLX3397, PLX7486, PLX8394, PLX9486, PRN1008, PRN1371, RXDX103, RXDX106, RXDX108, and TG101209 (N-tert-butyl-3-(5-methyl- 2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-4-ylamino)benzenesulfonamide). In some embodiments, the Ras-Raf-MEK-ERK pathway inhibitor is one or more of a BRAF inhibitor, a MEK inhibitor, and an ERK inhibitor. In some embodiments, the BRAF inhibitor is vemurafenib (ZELBORAF®), dabrafenib (TAFINLAR®) and encorafenib (BRAFTOVI ^™ ), BMS-908662 (XL281 ), Sorafenib, LGX818, PLX3603, RAF265, RO5185426, GSK2118436, ARQ 736, GDC-0879, PLX-4720, AZ304, PLX-8394, HM95573, RO5126766 and LXH254. In some embodiments, the MEK inhibitor is trametinib (MEKINIST®, GSK1120212), cobimetinib (COTELLIC®), vinimetinib (MEKTOVI®, MEK162), selumeti Nip (AZD6244), PD0325901, MSC1936369B, SHR7390, TAK-733, RO5126766, CS3006, WX-554, PD98059, CI1040 (PD184352) and at least one of hypothemycin. In some embodiments, the ERK inhibitor is FRI-20 (ON-01060), VTX-11e, 25-OH-D3-3-BE (B3CD, bromoacetoxycalcidiol), FR-180204, AEZ-131 ( AEZS-131), AEZS-136, AZ-13767370, BL-EI-001, LY-3214996, LTT-462, KO-947, KO-947, MK-8353 (SCH900353), SCH772984, Ullisertinib (BVD- 523), CC-90003, GDC-0994 (RG-7482), ASN007, FR148083, 5-7-oxozeaenol, 5-iodotubercidine, GDC0994, and ONC201. In some embodiments, the PI3K-Akt-mTOR-S6K pathway inhibitor is an AKT inhibitor. Non-limiting examples of AKT inhibitors include miltefosin (IMPADIVO®), wortmannin, NL-71-101, H-89, GSK690693, CCT128930, AZD5363, ifatasertip (GDC-0068, RG7440), A-674563, A-443654, AT7867, AT13148, Uprosertip, Apuressertip, DC120, 2-[4-(2-aminoprop-2-yl)phenyl]-3-phenylquinoxaline, MK -2206, edelfosin, miltefosin, perifosin, erucylphosphocholine, eruposin, SR13668, OSU-A9, PH-316, PHT-427, PIT-1, DM-PIT-1, tricyribine (tricy Ribine phosphate monohydrate), API-1, N-(4-(5-(3-acetamidophenyl)-2-(2-aminopyridin-3-yl)-3H-imidazo[4,5-b ]Pyridin-3-yl)benzyl)-3-fluorobenzamide, ARQ092, BAY 1125976, 3-oxo-tyrucalcic acid, lactoquinomycin, boc-Phe-vinyl ketone, perifosine (D-21266), TCN , TCN-P, GSK2141795 and ONC201. In some embodiments, the PI3K-Akt-mTOR-S6K pathway inhibitor is one or more of a PI3K inhibitor, an AKT inhibitor, and an mTOR inhibitor. In some embodiments, the PI3K-Akt-mTOR-S6K pathway inhibitor is a PI3K inhibitor. Non-limiting examples of PI3K inhibitors include buparlisib (BKM120), alfelissib (BYL719), WX-037, copanlisib (ALIQOPA ^TM , BAY80-6946), doctolisib (NVP-BEZ235, BEZ- 235), Tasselship (GDC-0032, RG7604), Sonoliship (PX-866), CUDC-907, PQR309, ZSTK474, SF1126, AZD8835, GDC-0077, ASN003, Pictiliship (GDC-0941), Pilarship (XL147, SAR245408), Gedatolyship (PF-05212384, PKI-587), Serapheliship (TAK-117, MLN1117, INK 1117), BGT-226 (NVP-BGT226), PF-04691502, Ah Phytolyship (GDC-0980), Omipallyship (GSK2126458, GSK458), Voxtality (XL756, SAR245409), AMG 511, CH5132799, GSK1059615, GDC-0084 (RG7666), VS-5584 (SB2343), PKI-402 , Wortmannin, LY294002, PI-103, igosertip, XL-765, LY2023414, SAR260301, KIN-193 (AZD-6428), GS-9820, AMG319 and GSK2636771. In some embodiments, the dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of these comprises expression of BTK-C. In some embodiments, BTK-C is expressed in prostate cancer or breast cancer. In some embodiments, the PI3K-Akt-mTOR-S6K pathway inhibitor is an AKT inhibitor. Non-limiting examples of AKT inhibitors include miltefosin (IMPADIVO®), wortmannin, NL-71-101, H-89, GSK690693, CCT128930, AZD5363, ifatasertip (GDC-0068, RG7440), A-674563, A-443654, AT7867, AT13148, Uprosertip, Apuressertip, DC120, 2-[4-(2-aminoprop-2-yl)phenyl]-3-phenylquinoxaline, MK -2206, edelfosin, miltefosin, perifosin, erucylphosphocholine, eruposin, SR13668, OSU-A9, PH-316, PHT-427, PIT-1, DM-PIT-1, tricyribine (tricy Ribine phosphate monohydrate), API-1, N-(4-(5-(3-acetamidophenyl)-2-(2-aminopyridin-3-yl)-3H-imidazo[4,5-b ]Pyridin-3-yl)benzyl)-3-fluorobenzamide, ARQ092, BAY 1125976, 3-oxo-tyrucalcic acid, lactoquinomycin, boc-Phe-vinyl ketone, perifosine (D-21266), TCN , TCN-P, GSK2141795 and ONC201. In some embodiments, the PI3K-Akt-mTOR-S6K pathway inhibitor is an mTOR inhibitor. Non-limiting examples of mTOR inhibitors include MLN0128, AZD-2014, CC-223, AZD2014, CC-115, everolimus (RAD001), temsirolimus (CCI-779), lidaforolimus (AP-23573) and Si. Contains lolimus (rapamycin).

Non-limiting examples of checkpoint inhibitors include ipilimumab, tremelimumab, nivolumab, pidilizumab, MPDL3208A, MEDI4736, MSB0010718C, BMS-936559, BMS-956559, BMS-935559 (MDX-1105), AMP-224 and Includes pembrolizumab.

In some embodiments, the protein inhibitor is an anti-apoptotic protein (e.g., Bcl family, such as BCL-2, BCL-X _L , BCL-W, BCL-B, and MCL1), heat shock protein (e.g., Hsp10 , Hsp27, HspB6, HspB1, Hsp40, Hsp60, Hsp71, Hsp70, Hsp72, Grp78 (BiP), Hsx70, Hsp90, Grp94, Hsp104, Hsp110), nuclear efflux protein (e.g., XPO1), histone deacetylase (HDAC1 , HDAC2, HDAC3, HDAC8, HDAC4, HDAC5, HDAC7, HDAC6, HDAC10, SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, SIRT7, and HDAC11), E3 ubiquitin ligase (e.g., E3A, MDM2, late- Promoting Complex (APC), UBR5 (EDD1), SOCS/ BC-box/ eloBC/ CUL5/ RING, LNXp80, CBX4, CBLL1, HACE1, HECTD1, HECTD2, HECTD3, HECTD4, HECW1, HECW2, HERC1, HERC2, HERC3, HERC4, HERC5, HERC6, HUWE1, ITCH, NEDD4, NEDD4L, PPIL2, PRPF19, PIAS1, PIAS2, PIAS3, PIAS4, RANBP2, RNF4, RBX1, SMURF1, SMURF2, STUB1, TOPORS, TRIP12, UBE3A, UBE3 UBE4A, UBE4B, UBOX5, UBR5, WWP1, WWP2, and Parkin), and histone-lysine N-methyltransferase (e.g., ASH1L, DOT1L, EHMT1, EHMT2, EZH1, EZH2, EHMT2, MLL, MLL2, MLL3 , MLL4, MLL5, NSD1, PRDM2, SET, SETBP1, SETD1A, SETD1B, SETD2, SETD3, SETD4, SETD5, SETD6, SETD7, SETD8, SETD9 , SETDB1, SETDB2, SETMAR, SMYD1, SMYD2, SMYD3, SMYD4, SMYD5, SUV39H1, SUV39H2, SUV420H1, and SUV420H2).

In some embodiments, the protein inhibitor is an agent that inhibits Bcl-2. Non-limiting examples of Bcl-2 inhibitors include venetoclax (ABT-199, RG7601, GDC-0199), navitoclax (ABT-263), ABT-737, TW-37, sabutoclax and obatoclax Includes su. Further examples of Bcl-2 inhibitors include the compounds described in International Publication No. WO 2018/195450.

In some embodiments, the protein inhibitor is an agent that inhibits EHMT2. Non-limiting examples of EHMT2 inhibitors include BIX-01294 (BIX), UNC0638, A-366, UNC0642, DCG066, UNC0321, BRD 4770, UNC 0224, UNC 0646, UNC0631, BIX-01338 and EZM8266.

In some embodiments, the protein inhibitor is PI3K, JAK-2, IRAK1, IRAK4, BMX, TAK1, Src family, HDAC6, MDM2, BCL-2, EZH2, EHMT2, PIM, JAK3, mTOR, ROR-1, Syk, PKC , HSP90, XPO1 and combinations thereof.

In some embodiments, the cytotoxic chemotherapeutic agent is arsenic trioxide, bleomycin, cabazitaxel, capecitabine, carboplatin, cisplatin, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, docetaxel, doxorubicin, eto Poside, fluorouracil, gemcitabine, irinotecan, lomustine, methotrexate, mitomycin C, oxaliplatin, paclitaxel, pemetrexed, temozolomide and vincristine.

Non-limiting examples of angiogenesis-targeted therapy include aflibercept and bevacizumab.

In some embodiments, the immunotherapy is cellular immunotherapy (eg, adoptive T-cell therapy, dendritic cell therapy, natural killer cell therapy). In some embodiments, the cellular immunotherapy is sipuleucel-T (APC8015; PROVENGE™; Plosker (2011) Drugs 71(1): 101-108). In some embodiments, cellular immunotherapy includes cells expressing a chimeric antigen receptor (CAR). In some embodiments, the cellular immunotherapy is CAR-T cell therapy. In some embodiments, the CAR-T cell therapy is tisagenrexel (KYMRIAH™).

In some embodiments, the immunotherapy is antibody therapy (eg, monoclonal antibody, conjugated antibody). In some embodiments, the antibody therapy is bevacizumab (MVASTI™, AVASTIN®), trastuzumab (HERCEPTIN®), avelumab (BAVENCIO®), rituximab (MabThera (MABTHERA)™, RITUXAN®), edrecolomab (Panorex), daratumumab (DARZALEX®), olaratumab (LARTRUVO™), o Patumumab (ARZERRA®), Alemtuzumab (CAMPATH®), Cetuximab (ERBITUX®), Oregobomab, Pembrolizumab (KEYTRUDA®) ), dinutuximab (UNITUXIN®), obinutuzumab (GAZYVA®), tremelimumab (CP-675,206), ramucirumab (CYRAMZA®), right Blituximab (TG-1101), Panitumumab (VECTIBIX®), Elotuzumab (EMPLICITI™), Avelumab (BAVENCIO®), Necitumumab ( PORTRAZZA™), sirtuzumab (UC-961), ibritumomab (ZEVALIN®), isutuximab (SAR650984), nimotuzumab, presolimumab (GC1008), Ririlumab (INN), Mogamulizumab (POTELIGEO®), Piclatuzumab (AV-299), Denosumab (XGEVA®), Ganitumab, Urelumab, Pidilizumab , Or Amatuximab.

In some embodiments, the immunotherapy is an antibody-drug conjugate. In some embodiments, the antibody-drug conjugate is gemtuzumab ozogamicin (MYLOTARG™), inotuzumab ozogamicin (BESPONSA®), brentuximab vedotin (adset ADCETRIS®), ado-trastuzumab emtansine (TDM-1; KADCYLA®), mirbetuximab sorabtansine (IMGN853), or anetumab labtansine.

In some embodiments, the immunotherapy comprises blinatumomab (AMG103; BLINCYTO®) or midostaurin (Rydapt).

In some embodiments, immunotherapy includes toxins. In some embodiments, the immunotherapy is denileukin diftitox (ONTAK®).

In some embodiments, the immunotherapy is cytokine therapy. In some embodiments, the cytokine therapy is interleukin 2 (IL-2) therapy, interferon alpha (IFNα) therapy, granulocyte colony stimulating factor (G-CSF) therapy, interleukin 12 (IL-12) therapy, interleukin 15 (IL-15 ) Therapy, interleukin 7 (IL-7) therapy or erythropoietin-alpha (EPO) therapy. In some embodiments, the IL-2 therapy is an aldesleukin (PROLEUKIN®). In some embodiments, the IFNa therapy is Introna® (ROFERON-A®). In some embodiments, the G-CSF therapy is filgrastim (NEUPOGEN®).

In some embodiments, the immunotherapy is an immune checkpoint inhibitor. In some embodiments, the immunotherapy comprises one or more immune checkpoint inhibitors. In some embodiments, the immune checkpoint inhibitor is a CTLA-4 inhibitor, a PD-1 inhibitor, or a PD-L1 inhibitor. In some embodiments, the CTLA-4 inhibitor is ipilimumab (YERVOY®) or tremelimumab (CP-675,206). In some embodiments, the PD-1 inhibitor is pembrolizumab (KEYTRUDA®) or nivolumab (OPDIVO®). In some embodiments, the PD-L1 inhibitor is atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®) or durvalumab (IMFINZI™).

In some embodiments, the immunotherapy is an mRNA-based immunotherapy. In some embodiments, the mRNA-based immunotherapy is CV9104 (see, e.g., Rausch et al. (2014) Human Vaccin Immunother 10(11): 3146-52; And Kubler et al. (2015) J. Immunother Cancer 3:26).

In some embodiments, the immunotherapy is Bacillus Calmet-Guereng (BCG) therapy.

In some embodiments, the immunotherapy is oncolytic virus therapy. In some embodiments, the oncolytic virus therapy is Talimogen Raherparebbeck (T-VEC; IMLYGIC®).

In some embodiments, the immunotherapy is a cancer vaccine. In some embodiments, the cancer vaccine is a human papillomavirus (HPV) vaccine. In some embodiments, the HPV vaccine is GARDASIL®, Gardasil9® or CERVARIX®. In some embodiments, the cancer vaccine is a hepatitis B virus (HBV) vaccine. In some embodiments, the HBV vaccine is ENGERIX-B®, RECOMBIVAX HB® or GI-13020 (TARMOGEN®). In some embodiments, the cancer vaccine is TWINRIX® or PEDIARIX®. In some embodiments, the cancer vaccine is BIOVAXID®, ONCOPHAGE®, GVAX, ADXS11-001, ALVAC-CEA, PROSTVAC®, RINDOPEPIMUT®, Sima Box-EGF, Lapuleucel-T (APC8024; NEUVENGE™), GRNVAC1, GRNVAC2, GRN-1201, Hepcortespenlisimut-L (Hepco-V5), DCVAX®, SCIB1, BMT CTN 1401, PrCa VBIR, PANVAC, PROSTATAK®, DPX-Survivac, or Viagen Fumatocell-L (HS-110).

In some embodiments, the immunotherapy is a peptide vaccine. In some embodiments, the peptide vaccine is Nelifepimut-S (E75) (NEUVAX™), IMA901 or SerboxM (SVN53-67). In some embodiments, the cancer vaccine is an immunogenic individual neoantigen vaccine (eg, Ott et al. (2017) Nature 547: 217-221; Sahin et al. (2017) Nature 547: 222-226). Reference). In some embodiments, the cancer vaccine is RGSH4K or NEO-PV-01. In some embodiments, the cancer vaccine is a DNA-based vaccine. In some embodiments, the DNA-based vaccine is a mammaglobin-A DNA vaccine (see, eg, Kim et al. (2016) OncoImmunology 5(2): e1069940).

In some embodiments, the immune-targeting agent is selected from aldesleukin, interferon alpha-2b, ipilimumab, lambrolizumab, nivolumab, prednisone and sipuleucel-T.

Non-limiting examples of radiotherapy include radioiodide therapy, external-beam radiation, and radium 223 therapy.

Additional kinase inhibitors are described, for example, in US Pat. 7,863,289; 8,026,247; 8,501,756; 8,552,002; 8,815,901; 8,912,204; 9,260,437; 9,273,051; US Publication No. US 2015/0018336; International Publication No. WO 2007/002325; WO 2007/002433; WO 2008/080001; WO 2008/079906; WO 2008/079903; WO 2008/079909; WO 2008/080015; WO 2009/007748; WO 2009/012283; WO 2009/143018; WO 2009/143024; WO 2009/014637; 2009/152083; WO 2010/111527; WO 2012/109075; WO 2014/194127; WO 2015/112806; WO 2007/110344; WO 2009/071480; WO 2009/118411; WO 2010/031816; WO 2010/145998; WO 2011/092120; WO 2012/101032; WO 2012/139930; WO 2012/143248; WO 2012/152763; WO 2013/014039; WO 2013/102059; WO 2013/050448; WO 2013/050446; WO 2014/019908; WO 2014/072220; WO 2014/184069; And WO 2016/075224, all of which are incorporated herein by reference in their entirety.

Further examples of kinase inhibitors are described, for example, in WO 2016/081450; WO 2016/022569; WO 2016/011141; WO 2016/011144; WO 2016/011147; WO 2015/191667; WO 2012/101029; WO 2012/113774; WO 2015/191666; WO 2015/161277; WO 2015/161274; WO 2015/108992; WO 2015/061572; WO 2015/058129; WO 2015/057873; WO 2015/017528; WO/2015/017533; WO 2014/160521; And WO 2014/011900, each of which is incorporated herein by reference in its entirety.

Further examples of kinase inhibitors are luminespib (AUY-922, NVP-AUY922) (5-(2,4-dihydroxy-5-isopropylphenyl)-N-ethyl-4-(4-(morpholino Methyl)phenyl)isoxazole-3-carboxamide) and doramapimod (BIRB-796) (1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[ 4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea).

Thus, (a) a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, spray-dried dispersion thereof for simultaneous, separate or sequential use for cancer treatment to a subject in need of treatment of cancer Administering a pharmaceutical combination for treating cancer comprising water or a pharmaceutical composition thereof, (b) an additional therapeutic agent and (c) optionally at least one pharmaceutically acceptable carrier, wherein Also herein is a method of treating cancer, wherein the amount of a compound or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical composition thereof and an additional therapeutic agent together is effective to treat cancer. Is provided.

In some embodiments, the additional therapeutic agent(s) comprises any of the therapies or therapeutics listed above, which are standard care in cancer with dysregulation of the expression or activity or level of the BTK gene, BTK protein, or any of these. .

These additional therapeutic agents, together with one or more doses of a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical composition thereof, as part of the same or separate dosage forms. , Via the same or different routes of administration, and/or with the same or different dosing schedules according to standard pharmaceutical practice known to those skilled in the art.

(i) for simultaneous, separate or sequential use for the treatment of cancer (a) a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form, spray-dried dispersion thereof or a pharmaceutical composition thereof, ( b) at least one additional therapeutic agent (e.g., any exemplary additional therapeutic agent described herein or known in the art) and (c) optionally at least one pharmaceutically acceptable carrier, Wherein the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof, amorphous or polymorphic form, a spray-dried dispersion thereof or a pharmaceutical composition thereof and an additional therapeutic agent is effective to treat cancer together Pharmaceutical combinations for treating cancer in a subject with; (ii) pharmaceutical compositions comprising such combinations; (iii) the use of such a combination for the manufacture of a medicament for the treatment of cancer; And (iv) a commercial package or product comprising such a combination as a combination formulation for simultaneous, separate or sequential use; And methods of treating cancer in a subject in need thereof are also provided herein. In one embodiment, the subject is a human. In some embodiments, the cancer is a BTK-associated cancer. For example, a BTK-associated cancer has one or more BTK inhibitor resistance mutations.

Thus, (a) a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, spray-dried dispersion thereof for simultaneous, separate or sequential use for cancer treatment to a subject in need of treatment of cancer Administering a pharmaceutical combination for treating cancer comprising water or a pharmaceutical composition thereof, (b) an additional therapeutic agent and (c) optionally at least one pharmaceutically acceptable carrier, wherein Also herein is a method of treating cancer, wherein the amount of a compound or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical combination thereof and an additional therapeutic agent together is effective to treat cancer. Is provided in. In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical combination thereof and the additional therapeutic agent are administered simultaneously as separate dosages. In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof and the additional therapeutic agent are administered sequentially in any order as individual dosages, in a combined therapeutically effective amount, e.g. daily or intermittently. It is administered in doses. In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical combination thereof and the additional therapeutic agent are administered simultaneously as a combined dosage. In some embodiments, the cancer is a BTK-associated cancer. For example, a BTK-associated cancer has one or more BTK inhibitor resistance mutations. In some embodiments, the additional therapeutic agent is ibrutinib. In some embodiments, the additional therapeutic agent is acalabrutinib. In some embodiments, the subject has been administered one or more doses of a compound of Formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof, prior to administration of the pharmaceutical composition.

Administration of a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form, spray-dried dispersion thereof or a pharmaceutical composition thereof to a subject in need of treatment of a disease or disorder mediated by BTK Also provided herein is a method of treating a disease or disorder mediated by BTK in said subject comprising the step of: In some embodiments, the disease or disorder mediated by BTK is dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of these. For example, dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of these comprises one or more BTK inhibitor resistance mutations. Diseases or disorders mediated by BTK may include any disease, disorder or condition directly or indirectly associated with the expression or activity of BTK, including overexpression and/or abnormal levels of activity. In one embodiment, the disease is cancer (eg, BTK-associated cancer). In one embodiment, the cancer is any cancer or BTK-associated cancer described herein. In some embodiments, the additional therapeutic agent is ibrutinib. In some embodiments, the additional therapeutic agent is acalabrutinib. In some embodiments, the subject has been administered one or more doses of a compound of Formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof, prior to administration of the pharmaceutical composition. In some embodiments, the cancer is a hematological cancer (eg, BTK-associated hematologic cancer).

Accordingly, a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof to a subject in need of suppressing, preventing, assisting or reducing symptoms of cancer metastasis, or Also provided herein is a method of inhibiting, preventing, assisting in preventing or reducing symptoms of cancer metastasis in the subject, comprising administering a pharmaceutical composition thereof. These methods can be used to treat one or more of the cancers described herein. In some embodiments, the cancer is a BTK-associated cancer. In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof is an additional therapy or another therapeutic agent, e.g., a chemotherapeutic agent, For example, it is used in combination with a kinase inhibitor, eg a first or second BTK kinase inhibitor. In some embodiments, the additional therapeutic agent is ibrutinib. In some embodiments, the additional therapeutic agent is acalabrutinib. In some embodiments, the subject has been administered one or more doses of a compound of Formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof, prior to administration of the pharmaceutical composition. In some embodiments, the cancer is lung cancer (eg, BTK-associated lung cancer).

Selecting, identifying or diagnosing a subject with BTK-associated cancer, and to a subject selected, identified or diagnosed as having BTK-associated cancer, a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorph thereof Also provided is a method of reducing the risk of developing metastasis or further metastasis in a subject with BTK-associated cancer comprising administering a form, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. BTK-associated cancer comprising administering to a subject having a BTK-associated cancer a therapeutically effective amount of Formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. Also provided are methods of reducing the risk of developing metastasis or further metastasis in a subject having. The reduction in the risk of developing metastases or further metastases in a subject with BTK-associated cancer can be compared to the risk of developing metastases or further metastases in a subject prior to treatment, or similar or identical not receiving treatment or receiving a different treatment. It can be compared to a subject or population of subjects with BTK-associated cancer. In some embodiments, the BTK-associated cancer is a BTK-associated cancer having one or more BTK inhibitor resistance mutations. In some embodiments, the additional therapeutic agent is ibrutinib. In some embodiments, the additional therapeutic agent is acalabrutinib. In some embodiments, the subject has been administered one or more doses of a compound of Formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof, prior to administration of the pharmaceutical composition. In some embodiments, the cancer is lung cancer (eg, BTK-associated lung cancer).

In some embodiments, the presence of one or more BTK inhibitor resistant mutations in the tumor makes the tumor more resistant to treatment with the first BTK inhibitor. Methods useful when the BTK inhibitor resistance mutation makes the tumor more resistant to treatment with the first BTK inhibitor are described below. For example, identifying a subject having cancer cells with one or more BTK inhibitor resistance mutations; And administering to the identified subject a compound of Formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. Is provided herein. In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof is administered in combination with a first BTK inhibitor. Administering a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form, spray-dried dispersion thereof, or a pharmaceutical composition thereof to a subject identified as having cancer cells with one or more BTK inhibitor resistance mutations Also provided is a method of treating the subject, comprising the step. In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof is administered in combination with a first BTK inhibitor. In some embodiments, the one or more BTK inhibitor resistance mutations confer increased resistance to treatment with the first BTK inhibitor to the cancer cell or tumor. In some embodiments, the one or more BTK inhibitor resistance mutations comprise one or more BTK inhibitor resistance mutations listed in Tables 2 and 3. For example, the one or more BTK inhibitor resistance mutations include substitutions at amino acid position 481, such as C481S, C481F, C481T, C481G and C481R, or substitutions at amino acid position 474, such as T474I, T474M and T474S. can do. As another example, one or more BTK inhibitor resistance mutations may be substituted in PLCγ2 (e.g., amino acid positions 244, 257, 334, 495, 664, 665, 707, 708, 742, 845, 848, 993, 1140 or 1141 Substitution in) may be included. In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof is an additional therapeutic agent that inhibits the upstream protein of BTK in the BCR signaling pathway. It is administered in combination with. In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof is an additional therapeutic agent that inhibits a protein downstream of BTK in the BCR signaling pathway. It is administered in combination with. In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof is an additional therapeutic agent that inhibits a protein downstream of BTK in the BCR signaling pathway. , E.g., in combination with a PLCy2 inhibitor, wherein one or more resistance mutations are within PLCy2 (e.g., amino acid positions 244, 257, 334, 495, 664, 665, 707, 708, 742, 845, 848, 993, 1140 or 1141).

For example, (a) detecting a dysregulation of the expression or activity or level of a BTK gene, a BTK kinase, or any of these in a sample from a subject in need of treatment of a BTK-associated cancer; And (b) administering to the subject a therapeutically effective amount of a first BTK inhibitor. In some embodiments, the first BTK inhibitor is Ibrutinib, PRN1008, PRN473, ABBV-105, AC0058, Acalabrutinib, Janubrutinib, Sfebrutinib, Foceltinib, Evobrutinib, Tirablutinib, CG '806, ARQ 531, BIIB068, Becabrutinib, AS871, CB1763, CB988, GDC-0853, RN486, GNE-504, GNE-309, BTK Max, Dasatinib, CT-1530, CGI-1746, CGI-560 , LFM A13, TP-0158, dtrmwxhs-12, CNX-774 and LOU064. In some embodiments, the first BTK inhibitor is a covalent inhibitor, e.g., ibrutinib, PRN1008, PRN473, ABBV-105, AC0058, Acalabrutinib, Janubrutinib, Sfebrutinib, Poceltinib, Evobrutinib , M7583 or tirabrutinib. In some embodiments, the first BTK inhibitor is a non-covalent inhibitor, for example CG'806, ARQ 531, BIIB068, becabrutinib, AS871, CB1763, CB988, GDC-0853, RN486 or Dasatinib. In some embodiments, the method comprises (after (b)) (c) determining whether the cancer cells in a sample obtained from the subject have at least one BTK inhibitor resistance mutation; And (d) when the subject has cancer cells having at least one BTK inhibitor resistance mutation, to the subject a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or Administering the pharmaceutical composition thereof as monotherapy or in combination with another anticancer agent; Or (e) if the subject has cancer cells that do not have a BTK inhibitor resistance mutation, administering to the subject an additional dose of the first BTK inhibitor of step (b).

In some embodiments, (a) detecting dysregulation of the expression or activity or level of a BTK gene, BTK kinase, or any of them in a sample from a subject in need of treatment of a BTK-associated cancer; And (b) administering to the subject a therapeutically effective amount of a first BTK inhibitor, wherein the first BTK inhibitor is ibrutinib, PRN1008, PRN473, ABBV-105, AC0058, Acalabrutinib, Janubrutinib. , Spebrutinib, Poceltinib, Evobrutinib, Tirabrutinib, CG'806, ARQ 531, BIIB068, Becabrutinib, AS871, CB1763, CB988, GDC-0853, RN486, GNE-504, GNE-309, BTK Max, dasatinib, CT-1530, CGI-1746, CGI-560, LFM A13, TP-0158, dtrmwxhs-12, CNX-774, and is selected from the group consisting of LOU064 BTK-associated cancer in the subject Provided herein are methods of treating. In some embodiments, the first BTK inhibitor is a covalent inhibitor, e.g., ibrutinib, PRN1008, PRN473, ABBV-105, AC0058, Acalabrutinib, Janubrutinib, Sfebrutinib, Poceltinib, Evobrutinib , M7583 or tirabrutinib. In some embodiments, the first BTK inhibitor is a non-covalent inhibitor, for example CG'806, ARQ 531, BIIB068, becabrutinib, AS871, CB1763, CB988, GDC-0853, RN486 or Dasatinib. In some embodiments, the method comprises (after (b)) (c) determining whether the cancer cells in a sample obtained from the subject have at least one BTK inhibitor resistance mutation; And (d) when the subject has cancer cells having at least one BTK inhibitor resistance mutation, to the subject a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or Administering the pharmaceutical composition thereof as monotherapy or in combination with another anticancer agent; Or (e) if the subject has cancer cells that do not have a BTK inhibitor resistance mutation, administering to the subject an additional dose of the first BTK inhibitor of step (b).

In some embodiments, the compound of Formula I is in polymorphic form. In some embodiments, the compound is polymorph Form A of the compound of formula (I). In some embodiments, the spray dried dispersion comprises a compound of Formula I and a HPMCAS polymer in a ratio of about 1:4 to about 4:1 of a compound of Formula I to HPMCAS polymer. In some embodiments, the spray dried dispersion comprises a compound of formula I and a HPMCAS polymer in a ratio of about 1:1 compound of formula I to HPMCAS polymer. In some embodiments, the HPMCAS polymer is HPMCAS-MG.

In some embodiments, (a) detecting at least one point mutation/insertion/deletion of Tables 1 and 4 in a sample from a subject in need of treatment of a BTK-associated cancer; And (b) administering to the subject a therapeutically effective amount of a first BTK inhibitor. In some embodiments, the first BTK inhibitor is Ibrutinib, PRN1008, PRN473, ABBV-105, AC0058, Acalabrutinib, Janubrutinib, Sfebrutinib, Foceltinib, Evobrutinib, Tirablutinib, CG '806, ARQ 531, BIIB068, Becabrutinib, AS871, CB1763, CB988, GDC-0853, RN486, GNE-504, GNE-309, BTK Max, Dasatinib, CT-1530, CGI-1746, CGI-560 , LFM A13, TP-0158, dtrmwxhs-12, CNX-774 and LOU064. In some embodiments, the first BTK inhibitor is a covalent inhibitor, e.g., ibrutinib, PRN1008, PRN473, ABBV-105, AC0058, Acalabrutinib, Janubrutinib, Sfebrutinib, Poceltinib, Evobrutinib , M7583 or tirabrutinib. In some embodiments, the first BTK inhibitor is a non-covalent inhibitor, for example CG'806, ARQ 531, BIIB068, becabrutinib, AS871, CB1763, CB988, GDC-0853, RN486 or Dasatinib. In some embodiments, the method comprises the steps of (after (b)) (c) determining whether the cancer cells in the sample obtained from the subject have at least one BTK inhibitor resistance mutation in Table 1 or 4; And (d) when the subject has cancer cells having at least one BTK inhibitor resistance mutation, to the subject a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or Administering the pharmaceutical composition thereof as monotherapy or in combination with another anticancer agent; Or (e) if the subject has cancer cells that do not have a BTK inhibitor resistance mutation, administering to the subject an additional dose of the first BTK inhibitor of step (b).

In some embodiments, the compound of Formula I is in polymorphic form. In some embodiments, the compound is polymorph Form A of the compound of formula (I). In some embodiments, the spray dried dispersion is as described herein.

In some embodiments, (a) detecting one or more BCR signaling pathway protein mutations of Table 4 in a sample from a subject in need thereof for treatment of BTK-associated cancer; And (b) administering to the subject a therapeutically effective amount of a first BTK inhibitor, wherein the first BTK inhibitor is ibrutinib, PRN1008, PRN473, ABBV-105, AC0058, Acalabrutinib, Janubrutinib. , Spebrutinib, Poceltinib, Evobrutinib, Tirabrutinib, CG'806, ARQ 531, BIIB068, Becabrutinib, AS871, CB1763, CB988, GDC-0853, RN486, GNE-504, GNE-309, BTK Max, dasatinib, CT-1530, CGI-1746, CGI-560, LFM A13, TP-0158, dtrmwxhs-12, CNX-774, and is selected from the group consisting of LOU064 BTK-associated cancer in the subject Provided herein are methods of treating. In some embodiments, the first BTK inhibitor is a covalent inhibitor, e.g., ibrutinib, PRN1008, PRN473, ABBV-105, AC0058, Acalabrutinib, Janubrutinib, Sfebrutinib, Poceltinib, Evobrutinib , M7583 or tirabrutinib. In some embodiments, the first BTK inhibitor is a non-covalent inhibitor, for example CG'806, ARQ 531, BIIB068, becabrutinib, AS871, CB1763, CB988, GDC-0853, RN486 or Dasatinib. In some embodiments, the method comprises (after (b)) (c) determining whether the cancer cells in the sample obtained from the subject have the BTK inhibitor resistance mutations C481S, C481F, C481T, C481G, C481R, T474I, T474M, or T474S. step; And (d) when the subject has cancer cells with at least one BTK inhibitor resistance mutation, to the subject a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or Administering a compound of formula (I) selected from the group consisting of pharmaceutical compositions thereof, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof as monotherapy or with another anticancer agent. ; Or (e) if the subject has cancer cells that do not have a BTK inhibitor resistance mutation, administering to the subject an additional dose of the first BTK inhibitor of step (b).

In some embodiments, the compound of Formula I is in polymorphic form. In some embodiments, the compound is polymorph Form A of the compound of formula (I). In some embodiments, the spray dried dispersion comprises a compound of Formula I and a HPMCAS polymer as described herein. In some embodiments, the HPMCAS polymer is HPMCAS-MG.

As another example, (a) detecting a dysregulation of the expression or activity or level of a BTK gene, a BTK kinase, or any of these in a sample from a subject in need of treatment of a BTK-associated cancer; And (b) administering to the subject a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. Provided herein are methods of treating associated cancer. In some embodiments, the method comprises (after (b)) (c) determining whether the cancer cells in a sample obtained from the subject have at least one BTK inhibitor resistance mutation; And (d) when the subject has cancer cells with at least one BTK inhibitor resistance mutation, administering to the subject a second BTK inhibitor as monotherapy or in combination with another anticancer agent, wherein the second BTK inhibitor is ibrutinib , PRN1008, PRN473, ABBV-105, AC0058, Acalabrutinib, Janubrutinib, Sfebrutinib, Porceltinib, Evobrutinib, Tirabrutinib, CG'806, ARQ 531, BIIB068, Becabrutinib, AS871 , CB1763, CB988, GDC-0853, RN486, GNE-504, GNE-309, BTK Max, Dasatinib, CT-1530, CGI-1746, CGI-560, LFM A13, TP-0158, dtrmwxhs-12, CNX -774 and LOU064; Or (e) if the subject has cancer cells that do not have a BTK inhibitor resistance mutation, the subject is given a compound of formula I of step (b) or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, spray-dried thereof. It further comprises administering an additional dose of the dispersion or pharmaceutical composition thereof. In some embodiments, (a) detecting dysregulation of the expression or activity or level of a BTK gene, BTK kinase, or any of them in a sample from a subject in need of treatment of a BTK-associated cancer; And (b) administering to the subject a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. -Provided herein are methods of treating associated cancer. In some embodiments, the method comprises (after (b)) (c) determining whether the cancer cells in a sample obtained from the subject have at least one BTK inhibitor resistance mutation; And (d) when the subject has cancer cells with at least one BTK inhibitor resistance mutation, administering to the subject a second BTK inhibitor as monotherapy or in combination with another anticancer agent, wherein the second BTK inhibitor is ibrutinib , PRN1008, PRN473, ABBV-105, AC0058, Acalabrutinib, Janubrutinib, Sfebrutinib, Porceltinib, Evobrutinib, Tirabrutinib, CG'806, ARQ 531, BIIB068, Becabrutinib, AS871 , CB1763, CB988, GDC-0853, RN486, GNE-504, GNE-309, BTK Max, Dasatinib, CT-1530, CGI-1746, CGI-560, LFM A13, TP-0158, dtrmwxhs-12, CNX -774 and LOU064; Or (e) if the subject has cancer cells that do not have a BTK inhibitor resistance mutation, the subject is given a compound of formula I of step (b) or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, spray-dried thereof. It further comprises administering an additional dose of the dispersion or pharmaceutical composition thereof.

In some embodiments, (a) detecting one or more BCR signaling pathway protein mutations of Table 4 in a sample from a subject in need thereof for treatment of BTK-associated cancer; And (b) administering to the subject a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. -Provided herein are methods of treating associated cancer. In some embodiments, the method comprises the steps of (after (b)) (c) determining whether the cancer cells in the sample obtained from the subject have at least one BTK inhibitor resistance mutation in Table 2; And (d) when the subject has cancer cells with at least one BTK inhibitor resistance mutation, administering to the subject a second BTK inhibitor as monotherapy or in combination with another anticancer agent, wherein the second BTK inhibitor is ibrutinib , PRN1008, PRN473, ABBV-105, AC0058, Acalabrutinib, Janubrutinib, Sfebrutinib, Porceltinib, Evobrutinib, Tirabrutinib, CG'806, ARQ 531, BIIB068, Becabrutinib, AS871 , CB1763, CB988, GDC-0853, RN486, GNE-504, GNE-309, BTK Max, Dasatinib, CT-1530, CGI-1746, CGI-560, LFM A13, TP-0158, dtrmwxhs-12, CNX -774 and LOU064; Or (e) if the subject has cancer cells that do not have a BTK inhibitor resistance mutation, the subject is given a compound of formula I of step (b), or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, spray-dried thereof. It further comprises administering an additional dose of the dispersion or pharmaceutical composition thereof. In some embodiments, (a) detecting ^{MYD88 L265P} in a sample from a subject in need of treatment of a BTK-associated cancer; And (b) administering to the subject a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. -Provided herein are methods of treating associated cancer. In some embodiments, the method comprises (after (b)) (c) determining whether the cancer cells in the sample obtained from the subject have the BTK inhibitor resistance mutations C481S, C481F, C481T, C481G, C481R, T474I, T474M, or T474S. step; And (d) when the subject has cancer cells with at least one BTK inhibitor resistance mutation, administering to the subject a second BTK inhibitor as monotherapy or in combination with another anticancer agent, wherein the second BTK inhibitor is ibrutinib , PRN1008, PRN473, ABBV-105, AC0058, Acalabrutinib, Janubrutinib, Sfebrutinib, Porceltinib, Evobrutinib, Tirabrutinib, CG'806, ARQ 531, BIIB068, Becabrutinib, AS871 , CB1763, CB988, GDC-0853, RN486, GNE-504, GNE-309, BTK Max, Dasatinib, CT-1530, CGI-1746, CGI-560, LFM A13, TP-0158, dtrmwxhs-12, CNX -774 and LOU064; Or (e) if the subject has cancer cells that do not have a BTK inhibitor resistance mutation, the subject is given a compound of formula I of step (b), or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, spray-dried thereof. It further comprises administering an additional dose of the dispersion or pharmaceutical composition thereof.

In some embodiments, (a) detecting at least one point mutation/insertion/deletion of Tables 1 and 4 in a sample from a subject in need of treatment of a BTK-associated cancer; And (b) administering to the subject a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. -Provided herein are methods of treating associated cancer. In some embodiments, the method comprises the steps of (after (b)) (c) determining whether the cancer cells in a sample obtained from the subject have at least one BTK inhibitor resistance mutation in Table 2; And (d) when the subject has cancer cells with at least one BTK inhibitor resistance mutation, administering to the subject a second BTK inhibitor as monotherapy or in combination with another anticancer agent, wherein the second BTK inhibitor is ibrutinib , PRN1008, PRN473, ABBV-105, AC0058, Acalabrutinib, Janubrutinib, Sfebrutinib, Porceltinib, Evobrutinib, Tirabrutinib, CG'806, ARQ 531, BIIB068, Becabrutinib, AS871 , CB1763, CB988, GDC-0853, RN486, GNE-504, GNE-309, BTK Max, Dasatinib, CT-1530, CGI-1746, CGI-560, LFM A13, TP-0158, dtrmwxhs-12, CNX -774 and LOU064; Or (e) if the subject has cancer cells that do not have a BTK inhibitor resistance mutation, the subject is given a compound of formula I of step (b) or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, spray-dried thereof. It further comprises administering an additional dose of the dispersion or pharmaceutical composition thereof.

As another example, (a) detecting a dysregulation of the expression or activity or level of a BTK gene, a BTK kinase, or any of these in a sample from a subject in need of treatment of a BTK-associated cancer; And (b) administering to the subject a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. Provided herein are methods of treating associated cancer. In some embodiments, the method comprises (after (b)) (c) determining whether the cancer cells in a sample obtained from the subject have at least one BTK inhibitor resistance mutation; And (d) when the subject has cancer cells with at least one BTK inhibitor resistance mutation, the subject is given a second therapeutic agent as monotherapy or a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, Administered with a spray-dried dispersion thereof or a pharmaceutical composition thereof, wherein the second therapeutic agent is selected from the group consisting of ibrutinib and acalabrutinib; Or (e) if the subject has cancer cells that do not have a BTK inhibitor resistance mutation, the subject is given a compound of formula I of step (b) or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, spray-dried thereof. It further comprises administering an additional dose of the dispersion or pharmaceutical composition thereof. In some embodiments, (a) one or more BTK kinase protein point mutations/insertions of Table 1 in a sample from a subject in need of treatment of BTK-associated cancer, BTK fusion of Table 1a, p65BTK, BTK-C, or Detecting at least one BTK mutation selected from the group consisting of at least one BCR signaling pathway gene mutation in Table 4; And (b) administering to the subject a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. -Provided herein are methods of treating associated cancer. In some embodiments, the method comprises the steps of (after (b)) (c) determining whether the cancer cells in a sample obtained from the subject have at least one BTK inhibitor resistance mutation in Table 2; And (d) when the subject has cancer cells with at least one BTK inhibitor resistance mutation, the subject is given a second therapeutic agent as monotherapy or a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, Administered with a spray-dried dispersion thereof or a pharmaceutical composition thereof, wherein the second therapeutic agent is selected from the group consisting of ibrutinib and acalabrutinib; Or (e) if the subject has cancer cells that do not have a BTK inhibitor resistance mutation, the subject is given a compound of formula I of step (b) or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, spray-dried thereof. It further comprises administering an additional dose of the dispersion or pharmaceutical composition thereof. In some embodiments, (a) detecting one or more BCR signaling pathway protein mutations of Table 4 in a sample from a subject in need thereof for treatment of BTK-associated cancer; And (b) administering to the subject a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. -Provided herein are methods of treating associated cancer. In some embodiments, the method comprises the steps of (after (b)) (c) determining whether the cancer cells in a sample obtained from the subject have at least one BTK inhibitor resistance mutation in Table 2; And (d) when the subject has cancer cells with at least one BTK inhibitor resistance mutation, the subject is given a second therapeutic agent as monotherapy or a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, Administered with a spray-dried dispersion thereof or a pharmaceutical composition thereof, wherein the second therapeutic agent is selected from the group consisting of ibrutinib and acalabrutinib; Or (e) if the subject has cancer cells that do not have a BTK inhibitor resistance mutation, the subject is given a compound of formula I of step (b) or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, spray-dried thereof. It further comprises administering an additional dose of the dispersion or pharmaceutical composition thereof. In some of the above embodiments, the BTK-associated cancer is a B-cell malignancy.

In some embodiments, the presence of one or more BTK inhibitor resistant mutations in the tumor makes the tumor more resistant to treatment with the first BTK inhibitor. Methods useful when the BTK inhibitor resistance mutation makes the tumor more resistant to treatment with the first BTK inhibitor are described below. For example, identifying a subject having cancer cells with one or more BTK inhibitor resistance mutations; And administering to the identified subject a compound of Formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. Is provided herein. In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof is administered in combination with a first BTK inhibitor. Administering a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form, spray-dried dispersion thereof, or a pharmaceutical composition thereof to a subject identified as having cancer cells with one or more BTK inhibitor resistance mutations Also provided is a method of treating the subject, comprising the step. In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof is administered in combination with a first BTK inhibitor. In some embodiments, the one or more BTK inhibitor resistance mutations confer increased resistance to treatment with the first BTK inhibitor to the cancer cell or tumor. In some embodiments, the one or more BTK inhibitor resistance mutations comprise one or more BTK inhibitor resistance mutations listed in Table 2. For example, the one or more BTK inhibitor resistance mutations include a substitution at amino acid position 481, e.g. C481S, C481F, C481T, C481G and C481R, or a substitution at amino acid position 474, e.g. T474I, T474M or T474S. can do. As another example, the one or more BTK inhibitor resistance mutations may comprise a substitution at amino acid positions 244, 257, 334, 495, 664, 665, 707, 708, 742, 845, 848, 993, 1140 or 1141 of PLCγ2. I can. In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof is an additional therapeutic agent that inhibits the upstream protein of BTK in the BCR signaling pathway. It is administered in combination with. In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof is an additional therapeutic agent that inhibits a protein downstream of BTK in the BCR signaling pathway. It is administered in combination with. In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof is an additional therapeutic agent that inhibits a protein downstream of BTK in the BCR signaling pathway. , E.g., in combination with a PLCy2 inhibitor, wherein one or more resistance mutations are within PLCy2 (e.g., amino acid positions 244, 257, 334, 495, 664, 665, 707, 708, 742, 845, 848, 993, 1140 or 1141).

In some embodiments, (a) detecting one or more BCR signaling pathway protein mutations of Table 4 in a sample from a subject in need thereof for treatment of BTK-associated cancer; And (b) administering to the subject a therapeutically effective amount of a first BTK inhibitor, wherein the first BTK inhibitor is ibrutinib, PRN1008, PRN473, ABBV-105, AC0058, Acalabrutinib, Janubrutinib. , Spebrutinib, Poceltinib, Evobrutinib, Tirabrutinib, CG'806, ARQ 531, BIIB068, Becabrutinib, AS871, CB1763, CB988, GDC-0853, RN486, GNE-504, GNE-309, BTK Max, Dasatinib, CT-1530, CGI-1746, CGI-560, LFM A13, TP-0158, dtrmwxhs-12, CNX-774 and LOU064; Or a pharmaceutically acceptable salt or solvate thereof. Provided herein is a method of treating BTK-associated cancer in the subject, which is selected from the group consisting of. In some embodiments, the method comprises the steps of (after (b)) (c) determining whether the cancer cells in a sample obtained from the subject have at least one BTK inhibitor resistance mutation in Table 2; And (d) when the subject has cancer cells having at least one BTK inhibitor resistance mutation, to the subject a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or Administering the pharmaceutical composition thereof as monotherapy or in combination with another anticancer agent; Or (e) if the subject has cancer cells that do not have a BTK inhibitor resistance mutation, administering to the subject an additional dose of the first BTK inhibitor of step (b).

In some embodiments, (a) detecting dysregulation of the expression or activity or level of a BTK gene, BTK kinase, or any of them in a sample from a subject in need of treatment of a BTK-associated cancer; And (b) administering to the subject a therapeutically effective amount of a first BTK inhibitor, wherein the first BTK inhibitor is ibrutinib, PRN1008, PRN473, ABBV-105, AC0058, Acalabrutinib, Janubrutinib. , Spebrutinib, Poceltinib, Evobrutinib, Tirabrutinib, CG'806, ARQ 531, BIIB068, Becabrutinib, AS871, CB1763, CB988, GDC-0853, RN486, GNE-504, GNE-309, BTK Max, Dasatinib, CT-1530, CGI-1746, CGI-560, LFM A13, TP-0158, dtrmwxhs-12, CNX-774 and LOU064; Or a pharmaceutically acceptable salt or solvate thereof. Provided herein is a method of treating BTK-associated cancer in the subject, which is selected from the group consisting of. In some embodiments, the method comprises (after (b)) (c) determining whether the cancer cells in a sample obtained from the subject have at least one BTK inhibitor resistance mutation; And (d) when the subject has cancer cells having at least one BTK inhibitor resistance mutation, to the subject a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or Administering the pharmaceutical composition thereof as monotherapy or in combination with another anticancer agent; Or (e) if the subject has cancer cells that do not have a BTK inhibitor resistance mutation, administering to the subject an additional dose of the first BTK inhibitor of step (b).

In some embodiments, (a) detecting dysregulation of the expression or activity or level of a BTK gene, BTK kinase, or any of them in a sample from a subject in need of treatment of a BTK-associated cancer; And (b) administering to the subject a therapeutically effective amount of a first BTK inhibitor, wherein the first BTK inhibitor is ibrutinib, PRN1008, PRN473, ABBV-105, AC0058, Acalabrutinib, Janubrutinib. , Spebrutinib, Poceltinib, Evobrutinib, Tirabrutinib, CG'806, ARQ 531, BIIB068, Becabrutinib, AS871, CB1763, CB988, GDC-0853, RN486, GNE-504, GNE-309, BTK Max, Dasatinib, CT-1530, CGI-1746, CGI-560, LFM A13, TP-0158, dtrmwxhs-12, CNX-774 and LOU064; Or a pharmaceutically acceptable salt or solvate thereof. Provided herein is a method of treating BTK-associated cancer in the subject, which is selected from the group consisting of. In some embodiments, the method comprises (after (b)) (c) determining whether the cancer cells in a sample obtained from the subject have at least one BTK inhibitor resistance mutation; And (d) when the subject has cancer cells having at least one BTK inhibitor resistance mutation, to the subject a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or Administering the pharmaceutical composition thereof as monotherapy or in combination with another anticancer agent; Or (e) if the subject has cancer cells that do not have a BTK inhibitor resistance mutation, administering to the subject an additional dose of the first BTK inhibitor of step (b).

In some embodiments, (a) one or more BTK kinase protein point mutations/insertions of Table 1 in a sample from a subject in need of treatment of BTK-associated cancer, BTK fusion of Table 1a, p65BTK, BTK-C, or Detecting at least one BTK mutation selected from the group consisting of at least one BCR signaling pathway gene mutation in Table 4; And (b) administering to the subject a therapeutically effective amount of a first BTK inhibitor, wherein the first BTK inhibitor is ibrutinib, PRN1008, PRN473, ABBV-105, AC0058, Acalabrutinib, Janubrutinib. , Spebrutinib, Poceltinib, Evobrutinib, Tirabrutinib, CG'806, ARQ 531, BIIB068, Becabrutinib, AS871, CB1763, CB988, GDC-0853, RN486, GNE-504, GNE-309, BTK Max, Dasatinib, CT-1530, CGI-1746, CGI-560, LFM A13, TP-0158, dtrmwxhs-12, CNX-774 and LOU064; Or a pharmaceutically acceptable salt or solvate thereof. Provided herein is a method of treating BTK-associated cancer in the subject, which is selected from the group consisting of. In some embodiments, the method comprises the steps of (after (b)) (c) determining whether the cancer cells in a sample obtained from the subject have at least one BTK inhibitor resistance mutation in Table 2; And (d) when the subject has cancer cells having at least one BTK inhibitor resistance mutation, to the subject a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or Administering the pharmaceutical composition thereof as monotherapy or in combination with another anticancer agent; Or (e) if the subject has cancer cells that do not have a BTK inhibitor resistance mutation, administering to the subject an additional dose of the first BTK inhibitor of step (b).

In some embodiments provided herein, the circulating tumor DNA is a specific therapy (e.g., a first BTK inhibitor, a second BTK inhibitor, or a compound of Formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, spray -Dried dispersions or pharmaceutical compositions thereof). For example, the therapy described herein (e.g., a first BTK inhibitor, a second BTK inhibitor, or a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or Before starting treatment with a pharmaceutical composition thereof), a biological sample can be obtained from a subject, and the level of circulating tumor DNA can be determined in the biological sample. This sample can be considered a baseline sample. The subject then receives one or more doses of a therapy as described herein (e.g., a first BTK inhibitor, a second BTK inhibitor, or a compound of Formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, Spray-dried dispersions or pharmaceutical compositions thereof) can be administered and the level of circulating tumor DNA can be monitored (e.g., after a first dose, a second dose, a third dose, etc. or after 1 week, 2 After a week, 3 weeks, 4 weeks, etc.) When the level of circulating tumor DNA is lower than the baseline sample (e.g., 1% to about 99% decrease, 1% to about 95% decrease, 1% to about 90% decrease, 1% to about 85% decrease, 1% to about 80% reduction, 1% to about 75% reduction, 1% reduction to about 70% reduction, 1% reduction to about 65% reduction, 1% reduction to about 60% reduction, 1% reduction to about 55% Decrease, 1% decrease to about 50% decrease, 1% decrease to about 45% decrease, 1% decrease to about 40% decrease, 1% decrease to about 35% decrease, 1% decrease to about 30% decrease, 1% decrease To about 25% decrease, 1% to about 20% decrease, 1% to about 15% decrease, 1% to about 10% decrease, 1% to about 5% decrease, about 5% to about 99% decrease, About 10% to about 99% reduction, about 15% to about 99% reduction, about 20% to about 99% reduction, about 25% to about 99% reduction, about 30% to about 99% reduction, about 35% to about 99% decrease, about 40% to about 99% decrease, about 45% to about 99% decrease, about 50% to about 99% decrease, about 55% to about 99% decrease, about 60% to about 99% decrease, about 65% to about 99% reduction, about 70% to about 99% reduction, about 75% to about 95% reduction, about 80% to about 99% reduction, about 90% reduction to about 99% reduction, about 95% to about 99% decrease, about 5% to about 10% decrease, about 5% to about 25% decrease, about 10% to about 30% decrease, about 20% to about 40% decrease, about 25% to about 50% decrease, about 35% to about 55% reduction, about 40% to about 60% reduction, about 50% reduction to about 75% reduction, about 60% reduction to about 80% reduction, or about 65% to about 85% reduction, etc.), which Shows responsiveness to therapy. In some embodiments, the level of circulating tumor DNA in a biological sample (n) obtained from a subject is compared to a sample (n-1) taken immediately previously. When the level of circulating tumor DNA in the n sample is lower than the n-1 sample (e.g., 1% to about 99% decrease, 1% to about 95% decrease, 1% to about 90% decrease, 1% to About 85% reduction, 1% to about 80% reduction, 1% to about 75% reduction, 1% reduction to about 70% reduction, 1% reduction to about 65% reduction, 1% reduction to about 60% reduction, 1% Decrease to about 55%, 1% to about 50%, 1% to about 45%, 1% to about 40%, 1% to about 35%, 1% to about 30% Decrease, 1% decrease to about 25% decrease, 1% decrease to about 20% decrease, 1% decrease to about 15% decrease, 1% decrease to about 10% decrease, 1% to about 5% decrease, about 5% to About 99% reduction, about 10% to about 99% reduction, about 15% to about 99% reduction, about 20% to about 99% reduction, about 25% to about 99% reduction, about 30% to about 99% reduction, About 35% to about 99% reduction, about 40% to about 99% reduction, about 45% to about 99% reduction, about 50% to about 99% reduction, about 55% to about 99% reduction, about 60% to about 99% decrease, about 65% to about 99% decrease, about 70% to about 99% decrease, about 75% to about 95% decrease, about 80% to about 99% decrease, about 90% decrease to about 99% decrease, About 95% to about 99% reduction, about 5% to about 10% reduction, about 5% to about 25% reduction, about 10% to about 30% reduction, about 20% to about 40% reduction, about 25% to about 50% reduction, about 35% to about 55% reduction, about 40% to about 60% reduction, about 50% reduction to about 75% reduction, about 60% reduction to about 80% reduction, or about 65% to about 85% Reduction, etc.), which indicates a responsiveness to therapy. If responsive to therapy, the subject may be administered one or more doses of therapy, and circulating tumor DNA may continue to be monitored.

When the level of circulating tumor DNA in the sample is higher than baseline (e.g., 1% to about 99% increase, 1% to about 95% increase, 1% to about 90% increase, 1% to about 85% increase , 1% to about 80% increase, 1% to about 75% increase, 1% increase to about 70% increase, 1% increase to about 65% increase, 1% increase to about 60% increase, 1% increase to about 55 % Increase, 1% increase to about 50% increase, 1% increase to about 45% increase, 1% increase to about 40% increase, 1% increase to about 35% increase, 1% increase to about 30% increase, 1% Increase to about 25% increase, 1% increase to about 20% increase, 1% increase to about 15% increase, 1% increase to about 10% increase, 1% to about 5% increase, about 5% to about 99% increase , From about 10% to about 99% increase, from about 15% to about 99% increase, from about 20% to about 99% increase, from about 25% to about 99% increase, from about 30% to about 99% increase, from about 35% to About 99% increase, about 40% to about 99% increase, about 45% to about 99% increase, about 50% to about 99% increase, about 55% to about 99% increase, about 60% to about 99% increase, About 65% to about 99% increase, about 70% to about 99% increase, about 75% to about 95% increase, about 80% to about 99% increase, about 90% increase to about 99% increase, about 95% to About 99% increase, about 5% to about 10% increase, about 5% to about 25% increase, about 10% to about 30% increase, about 20% to about 40% increase, about 25% to about 50% increase, About 35% to about 55% increase, about 40% to about 60% increase, about 50% increase to about 75% increase, about 60% increase to about 80% increase, or about 65% to about 85% increase, etc.), This can indicate resistance to therapy. When the level of circulating tumor DNA in the n sample is higher than the n-1 sample (e.g., 1% to about 99% increase, 1% to about 95% increase, 1% to about 90% increase, 1% to About 85% increase, 1% to about 80% increase, 1% to about 75% increase, 1% increase to about 70% increase, 1% increase to about 65% increase, 1% increase to about 60% increase, 1% Increase to about 55% increase, 1% increase to about 50% increase, 1% increase to about 45% increase, 1% increase to about 40% increase, 1% increase to about 35% increase, 1% increase to about 30% Increase, 1% increase to about 25% increase, 1% increase to about 20% increase, 1% increase to about 15% increase, 1% increase to about 10% increase, 1% to about 5% increase, about 5% increase About 99% increase, about 10% to about 99% increase, about 15% to about 99% increase, about 20% to about 99% increase, about 25% to about 99% increase, about 30% to about 99% increase, About 35% to about 99% increase, about 40% to about 99% increase, about 45% to about 99% increase, about 50% to about 99% increase, about 55% to about 99% increase, about 60% to about 99% increase, about 65% to about 99% increase, about 70% to about 99% increase, about 75% to about 95% increase, about 80% to about 99% increase, about 90% increase to about 99% increase, About 95% to about 99% increase, about 5% to about 10% increase, about 5% to about 25% increase, about 10% to about 30% increase, about 20% to about 40% increase, about 25% to about 50% increase, about 35% to about 55% increase, about 40% to about 60% increase, about 50% increase to about 75% increase, about 60% increase to about 80% increase, or about 65% to about 85% Increase, etc.), which may indicate resistance to therapy. If resistance to therapy is suspected, the subject may undergo one or more of imaging, biopsy, surgery, or other diagnostic tests. In some embodiments, when resistance to therapy is suspected, the subject is a compound capable of treating BTK inhibitor resistance (e.g., a compound of formula I as provided herein, or a pharmaceutically acceptable salt thereof, amorphous or polyvalent. Form form, spray-dried dispersions thereof or pharmaceutical compositions thereof) can be administered (either alone or in combination with previous therapies). See, eg, Cancer Discov; 7(12); 1368-70 (2017); And Cancer Discov; 7(12); 1394-403 (2017).

(a) confirmed or diagnosed to have a BTK-associated cancer (e.g., any type of BTK-associated cancer described herein) (e.g., any exemplary 1 or more (e.g., 2 or more, 3 or more, 4 or more, 5 or more, or 10 times or more of a first BTK kinase inhibitor) to a subject identified or diagnosed as having a BTK-associated cancer using the method. Or more) administering a dose; (b) after step (a), determining the level of circulating tumor DNA in a biological sample (eg, a biological sample comprising blood, serum or plasma) obtained from the subject; (c) a therapeutically effective amount of agent to a subject identified as having approximately the same or elevated levels of circulating tumor DNA compared to a reference level of circulating tumor DNA (e.g., a reference level of any circulating tumor DNA described herein). 2 Comprising the step of administering a BTK inhibitor or a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical composition thereof as monotherapy or with another anticancer agent, Also provided herein are methods of treating BTK-associated cancer in a subject. In some examples of these methods, the reference level of circulating tumor DNA is the level of circulating tumor DNA in a biological sample obtained from a subject prior to step (a). Some embodiments of these methods further comprise determining the level of circulating tumor DNA in the biological sample obtained from the subject prior to step (a). In some examples of these methods, the reference level of circulating tumor DNA is the limiting level of circulating tumor DNA (e.g., having similar BTK-associated cancer and similar stage of BTK-associated cancer, but receiving non-effective treatment or placebo or Average level of circulating tumor DNA in a population of subjects that have not yet received curative treatment or have similar BTK-associated cancers and have similar stage BTK-related cancers, but have received non-effective treatment or placebo or have not yet received curative treatment. The level of circulating tumor DNA in the non-subjects). In some examples of these methods, the first BTK inhibitor is ibrutinib, PRN1008, PRN473, ABBV-105, AC0058, Acalabrutinib, Janubrutinib, Sfebrutinib, Foceltinib, Evobrutinib, Tirabrutinib , CG'806, ARQ 531, BIIB068, Becabrutinib, AS871, CB1763, CB988, GDC-0853, RN486, GNE-504, GNE-309, BTK Max, Dasatinib, CT-1530, CGI-1746, CGI -560, LFM A13, TP-0158, dtrmwxhs-12, CNX-774 and LOU064. In other examples of these methods, the first BTK inhibitor is a covalent inhibitor or a non-covalent inhibitor. In some embodiments, the covalent inhibitor consists of Ibrutinib, PRN1008, PRN473, ABBV-105, AC0058, Acalabrutinib, Janubrutinib, Sfebrutinib, Foceltinib, Evobrutinib, M7583, and Tirablutinib. Is selected from the group. In some embodiments, the first BTK inhibitor is selected from the group consisting of CG'806, ARQ 531, BIIB068, Becabrutinib, AS871, CB1763, CB988, GDC-0853, RN486, and Dasatinib.

(i) have been identified or diagnosed as having a BTK-associated cancer (e.g., any type of BTK-associated cancer described herein) (e.g., any exemplary Confirmed or diagnosed to have a BTK-associated cancer using the method), (ii) at least once (e.g., at least 2, at least 3, at least 4, at least 5 or at least 10) A dose of a second BTK kinase inhibitor is administered, and (ii) after previous administration of one or more doses of the second BTK kinase inhibitor, the reference level of circulating tumor DNA (e.g., described herein or known in the art. A therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof to a subject identified as having approximately the same or elevated levels of circulating tumor DNA compared to the reference level of any circulating tumor DNA). Also provided herein is a method of treating BTK-associated cancer in a subject comprising administering a spray-dried dispersion thereof or a pharmaceutical composition thereof. In some embodiments of these methods, the reference level of circulating tumor DNA is a biological sample (e.g., a biological sample comprising blood, plasma or serum) obtained from a subject prior to administration of one or more doses of a second BTK kinase inhibitor. Is the level of DNA in the circulating tumor within. Some embodiments of these methods further comprise determining the level of circulating tumor DNA in a biological sample obtained from the subject prior to administration of one or more doses of a second BTK kinase inhibitor. In some examples of these methods, the reference level of circulating tumor DNA is the limiting level of circulating tumor DNA (e.g., having similar BTK-associated cancer and similar stage of BTK-associated cancer, but receiving non-effective treatment or placebo or Average level of circulating tumor DNA in a population of subjects that have not yet received curative treatment or have similar BTK-associated cancers and have similar stage BTK-related cancers, but have received non-effective treatment or placebo or have not yet received curative treatment. The level of circulating tumor DNA in the non-subjects). In some embodiments of these methods, the second BTK kinase inhibitor is Ibrutinib, PRN1008, PRN473, ABBV-105, AC0058, Acalabrutinib, Janubrutinib, Sfebrutinib, Poceltinib, Evobrutinib, Thira. Brutinib, CG'806, ARQ 531, BIIB068, Becabrutinib, AS871, CB1763, CB988, GDC-0853, RN486, GNE-504, GNE-309, BTK Max, Dasatinib, CT-1530, CGI-1746 , CGI-560, LFM A13, TP-0158, dtrmwxhs-12, CNX-774 and LOU064. In other embodiments of these methods, the second BTK inhibitor is a covalent inhibitor or a non-covalent inhibitor. In some embodiments, the covalent inhibitor consists of Ibrutinib, PRN1008, PRN473, ABBV-105, AC0058, Acalabrutinib, Janubrutinib, Sfebrutinib, Foceltinib, Evobrutinib, M7583, and Tirablutinib. Is selected from the group. In some embodiments, the second BTK inhibitor is selected from the group consisting of CG'806, ARQ 531, BIIB068, Becabrutinib, AS871, CB1763, CB988, GDC-0853, RN486, and Dasatinib.

(a) Subjects identified or diagnosed with BTK-associated cancer (e.g., any type of BTK-associated cancer described herein) (e.g., any method described herein or known in the art A compound of formula (I) or a pharmaceutically acceptable salt thereof, amorphous or polymorphic form, spray-dried dispersion thereof or a pharmaceutical thereof in one or more doses to a subject identified or diagnosed with BTK-associated cancer) using Administering the composition as a monotherapy; (b) after step (a), determining the level of circulating tumor DNA in a biological sample obtained from the subject (eg, a biological sample comprising blood, serum or plasma); (c) having an approximately equal or elevated level of circulating tumor DNA compared to a reference level of circulating tumor DNA (e.g., a reference level of any exemplary circulating tumor DNA described herein or known in the art). A therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical composition thereof and a further therapeutic agent or treatment (e.g., herein Also provided herein is a method of treating a BTK-associated cancer in a subject comprising administering any additional therapeutic or treatment of BTK-associated cancer described or known in the art. In some embodiments of these methods, the additional therapeutic agent is a second BTK kinase inhibitor (e.g., a shared BTK inhibitor or a non-shared BTK inhibitor, or ibrutinib, PRN1008, PRN473, ABBV-105, AC0058, Acalabru Tinib, Janubrutinib, Sfebrutinib, Poceltinib, Evobrutinib, Tirabrutinib, CG'806, ARQ 531, BIIB068, Becabrutinib, AS871, CB1763, CB988, GDC-0853, RN486, GNE-504 , GNE-309, BTK Max, Dasatinib, CT-1530, CGI-1746, CGI-560, LFM A13, TP-0158, dtrmwxhs-12, CNX-774 and a BTK kinase inhibitor selected from the group of LOU064). In some examples of any of these methods, the additional therapeutic agent or treatment is radiation therapy, a chemotherapeutic agent (e.g., any exemplary chemotherapeutic agent described herein or known in the art), a checkpoint inhibitor (e.g. For example, any exemplary checkpoint inhibitor described herein or known in the art), surgery (e.g., at least partial resection of a tumor), and one or more other kinase or protein inhibitors (e.g., herein And any exemplary kinase or protein inhibitor described in or known in the art). In some examples of these methods, the reference level of circulating tumor DNA is the level of circulating tumor DNA in a biological sample (eg, a biological sample comprising blood, serum or plasma) obtained from a subject prior to step (a). In some examples of these methods, the reference level of circulating tumor DNA is the limiting level of circulating tumor DNA (e.g., having similar BTK-associated cancer and similar stage of BTK-associated cancer, but receiving non-effective treatment or placebo or Average level of circulating tumor DNA in a population of subjects that have not yet received curative treatment or have similar BTK-associated cancers and have similar stage BTK-related cancers, but have received non-effective treatment or placebo or have not yet received curative treatment. The level of circulating tumor DNA in the non-subjects).

(i) have been identified or diagnosed as having a BTK-associated cancer (e.g., any type of BTK-associated cancer described herein) (e.g., any method described herein or known in the art) Subjects identified or diagnosed with BTK-associated cancer), (ii) previously at least one dose of a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof Water or a pharmaceutical composition thereof is administered as monotherapy, and (ii) a compound of formula I in a dose of at least one (e.g., at least 2, at least 3, at least 4, at least 5 or at least 10 times) Or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof, after administration as monotherapy, the reference level of circulating tumor DNA (e.g., any example described herein A therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, to a subject identified as having an approximately the same or an elevated level of circulating tumor DNA compared to a reference level of circulating tumor DNA). Also provided herein is a method of treating BTK-associated cancer in a subject comprising administering a spray-dried dispersion or pharmaceutical composition thereof and an additional therapeutic agent or treatment. In some embodiments of these methods, the reference level of circulating tumor DNA is one or more (e.g., 2 or more, 3 or more, 4 or more, 5 or more, or 10 or more) doses of a compound of formula I Or the level of circulating tumor DNA in a biological sample obtained from a subject prior to administration of a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof as monotherapy. Some embodiments of these methods include administration of one or more doses of a compound of Formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof from a subject prior to administration as monotherapy. It further comprises determining the level of circulating tumor DNA in the obtained biological sample. In some examples of these methods, the reference level of circulating tumor DNA is the limiting level of circulating tumor DNA (e.g., having similar BTK-associated cancer and similar stage of BTK-associated cancer, but receiving non-effective treatment or placebo or Average level of circulating tumor DNA in a population of subjects that have not yet received curative treatment or have similar BTK-associated cancers and have similar stage BTK-related cancers, but have received non-effective treatment or placebo or have not yet received curative treatment. The level of circulating tumor DNA in the non-subjects). In some embodiments of these methods, the additional therapeutic agent is a second BTK kinase inhibitor (e.g., a shared BTK inhibitor or a non-shared BTK inhibitor, or ibrutinib, PRN1008, PRN473, ABBV-105, AC0058, Acalabru Tinib, Janubrutinib, Sfebrutinib, Poceltinib, Evobrutinib, Tirabrutinib, CG'806, ARQ 531, BIIB068, Becabrutinib, AS871, CB1763, CB988, GDC-0853, RN486, GNE-504 , GNE-309, BTK Max, Dasatinib, CT-1530, CGI-1746, CGI-560, LFM A13, TP-0158, dtrmwxhs-12, CNX-774 and a second BTK kinase inhibitor selected from the group of LOU064) to be. In some embodiments of these methods, the additional therapeutic agent or treatment is radiation therapy, a chemotherapeutic agent (e.g., any exemplary chemotherapeutic agent described herein or known in the art), a checkpoint inhibitor (e.g. For example, any exemplary checkpoint inhibitor described herein or known in the art), surgery (e.g., at least partial resection of a tumor), and one or more other kinase or protein inhibitors (e.g., herein Any exemplary kinase or protein inhibitor described or known in the art).

(i) have been identified or diagnosed as having a BTK-associated cancer (e.g., any type of BTK-associated cancer described herein) (e.g., any exemplary Subjects identified or diagnosed as having BTK-associated cancer using the method), (ii) at least once (e.g., at least 2, at least 3, at least 4, at least 5 or at least 10 times) ) Of a second BTK kinase inhibitor (e.g., any BTK kinase inhibitor described herein or known in the art) is administered, and (ii) after administration of one or more doses of the second BTK kinase inhibitor , A therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, for a subject identified as having an approximately equal or elevated level of circulating tumor DNA compared to a reference level of circulating tumor DNA, Also provided herein is a method of selecting a treatment for a subject comprising the step of selecting a spray-dried dispersion or pharmaceutical composition thereof. In some embodiments of any of these methods, the reference level of circulating tumor DNA is a biological sample (e.g., comprising blood, serum or plasma) obtained from a subject prior to administration of one or more doses of a second BTK kinase inhibitor. Sample) is the level of circulating tumor DNA. Some embodiments of these methods further comprise determining the level of circulating tumor DNA in a biological sample obtained from the subject prior to administration of one or more doses of a second BTK kinase inhibitor. In some examples of these methods, the reference level of circulating tumor DNA is the limiting level of circulating tumor DNA (e.g., having similar BTK-associated cancer and similar stage of BTK-associated cancer, but receiving non-effective treatment or placebo or Average level of circulating tumor DNA in a population of subjects that have not yet received curative treatment or have similar BTK-associated cancers and have similar stage BTK-related cancers, but have received non-effective treatment or placebo or have not yet received curative treatment. The level of circulating tumor DNA in the non-subjects). In some embodiments of any of these methods, the second BTK kinase inhibitor is ibrutinib, PRN1008, PRN473, ABBV-105, AC0058, Acalabrutinib, Janubrutinib, Sfebrutinib, Foceltinib, Evobrutinib. , Tirabrutinib, CG'806, ARQ 531, BIIB068, Becabrutinib, AS871, CB1763, CB988, GDC-0853, RN486, GNE-504, GNE-309, BTK Max, Dasatinib, CT-1530, CGI -1746, CGI-560, LFM A13, TP-0158, dtrmwxhs-12, CNX-774 and LOU064. In some embodiments of these methods, the second BTK inhibitor is a covalent inhibitor or a non-covalent inhibitor. In some embodiments, the covalent inhibitor consists of Ibrutinib, PRN1008, PRN473, ABBV-105, AC0058, Acalabrutinib, Janubrutinib, Sfebrutinib, Foceltinib, Evobrutinib, M7583, and Tirablutinib. Is selected from the group. In some embodiments, the second BTK inhibitor is selected from the group consisting of CG'806, ARQ 531, BIIB068, Becabrutinib, AS871, CB1763, CB988, GDC-0853, RN486, and Dasatinib.

(i) have been identified or diagnosed to have a BTK-associated cancer (e.g., any type of BTK-associated cancer described herein or known in the art) (e.g., described herein or Subjects diagnosed or confirmed to have BTK-associated cancer using any of the exemplary methods known in the art), (ii) at least one dose previously (e.g., at least 2 times, at least 3 times, at least 4 times). , At least 5 times or at least 10 times) of a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical composition thereof is administered as monotherapy, (ii) 1 After administration of one or more doses of a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical composition thereof, approximately equal or elevated compared to the reference level of circulating tumor DNA. A therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical composition thereof and additional therapeutic agents for a subject identified as having a level of circulating tumor DNA Or, a method of selecting a treatment for a subject, comprising the step of selecting a treatment, is also provided herein. In some embodiments of these methods, the reference level of circulating tumor DNA comprises at least one dose of a compound of Formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. The level of circulating tumor DNA in a biological sample (eg, a biological sample comprising blood, serum or plasma) obtained from a subject prior to administration as monotherapy. Some embodiments include a biological obtained from a subject prior to administering one or more doses of a compound of Formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof as monotherapy. It further comprises determining the level of circulating tumor DNA in the sample. In some examples of these methods, the reference level of circulating tumor DNA is the limiting level of circulating tumor DNA (e.g., having similar BTK-associated cancer and similar stage of BTK-associated cancer, but receiving non-effective treatment or placebo or Average level of circulating tumor DNA in a population of subjects that have not yet received curative treatment or have similar BTK-associated cancers and have similar stage BTK-related cancers, but have received non-effective treatment or placebo or have not yet received curative treatment. The level of circulating tumor DNA in the non-subjects). In some embodiments of any of these methods, the additional therapeutic agent is a second BTK kinase inhibitor (e.g., Ibrutinib, PRN1008, PRN473, ABBV-105, AC0058, Acalabrutinib, Janubrutinib, Spebru Tinib, Poceltinib, Evobrutinib, Tirablutinib, CG'806, ARQ 531, BIIB068, Becabrutinib, AS871, CB1763, CB988, GDC-0853, RN486, GNE-504, GNE-309, BTK Max, Da Satinib, CT-1530, CGI-1746, CGI-560, LFM A13, TP-0158, dtrmwxhs-12, CNX-774 and a second BTK kinase inhibitor selected from the group of LOU064). In some embodiments of these methods, the second BTK inhibitor is a covalent inhibitor or a non-covalent inhibitor. In some embodiments, the covalent inhibitor consists of Ibrutinib, PRN1008, PRN473, ABBV-105, AC0058, Acalabrutinib, Janubrutinib, Sfebrutinib, Foceltinib, Evobrutinib, M7583, and Tirablutinib. Is selected from the group. In some embodiments, the second BTK inhibitor is selected from the group consisting of CG'806, ARQ 531, BIIB068, Becabrutinib, AS871, CB1763, CB988, GDC-0853, RN486, and Dasatinib. In some embodiments of any of the methods described herein, the additional therapeutic agent or treatment is radiation therapy, a chemotherapeutic agent (e.g., any example of a chemotherapeutic agent described herein or known in the art), a checkpoint. Inhibitors (e.g., any checkpoint inhibitors described herein or known in the art), surgery (e.g., at least partial resection of a tumor), and one or more other kinase or protein inhibitors (e.g., Any other kinase or other protein inhibitor described herein or known in the art).

(a) Determining a first level of circulating tumor DNA in a biological sample (e.g., a biological sample comprising blood, serum or plasma) obtained from a subject identified or diagnosed with a BTK-associated cancer at the first time point. The step of doing; (b) After the first time point and before the second time point, the subject is given at least one dose of a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. Administering a treatment comprising; (c) determining a second level of circulating tumor DNA in a biological sample (eg, a biological sample comprising blood, serum or plasma) obtained from the subject at a second time point; And (d) confirming that the treatment is effective in a subject determined to have a reduced second level of circulating tumor DNA compared to the first level of circulating tumor DNA; Or confirming that the treatment is not effective in a subject determined to have a second level of circulating tumor DNA that is approximately the same or elevated compared to the first level of circulating tumor DNA. Methods are also provided herein. In some embodiments of these methods, the first time point and the second time point are about 1 week to about 1 year (e.g., about 1 week to about 10 months, about 1 week to about 8 months, about 1 week to about 6 months). Months, about 1 week to about 4 months, about 1 week to about 3 months, about 1 week to about 2 months, about 1 week to about 1 month, or about 1 week to about 2 weeks).

(a) Determining a first level of circulating tumor DNA in a biological sample (e.g., a biological sample comprising blood, serum or plasma) obtained from a subject identified or diagnosed with a BTK-associated cancer at the first time point. The step of doing; (b) after the first time point and before the second time point, to the subject at least one (e.g., at least 2, at least 3, at least 4, at least 5 or at least 10) doses of a compound of formula I, or Administering a treatment comprising a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof; (c) determining a second level of circulating tumor DNA in the biological sample obtained from the subject at a second time point; And (d) determining that a subject with a second level of circulating tumor DNA reduced compared to the first level of circulating tumor DNA has not developed resistance to treatment; Or determining that a subject with a second level of circulating tumor DNA that is approximately the same or elevated compared to the first level of circulating tumor DNA has developed resistance to treatment. A method of determining whether or not is also provided herein. In some embodiments of these methods, the first time point and the second time point are about 1 week to about 1 year (e.g., about 1 week to about 10 months, about 1 week to about 8 months, about 1 week to about 6 months). Months, about 1 week to about 4 months, about 1 week to about 3 months, about 1 week to about 2 months, about 1 week to about 1 month, or about 1 week to about 2 weeks).

Exemplary methods for detecting circulating tumor DNA are described in Moati et al., Clin. Res. Hepatol. Gastroenterol. April 4, 2018; Oussalah et al., EBioMedicine March 28, 2018; Moon et al., Adv. Drug Deliv. Rev. April 4, 2018; Solassaol et al., Clin. Chem. Lab. Med. April 7, 2018; Arriola et al., Clin. Transl. Oncol. April 5, 2018; Song et al., J. Circ. Biomark. March 25, 2018; Aslibekyan et al., JAMA Cardiol. April 4, 2018; Isbell et al., J. Thorac. Cardiovasc. Surg. March 13, 2018; Boeckx et al., Clin. Colorectal Cancer February 22, 2018; Anunobi et al., J. Surg. Res. March 28, 2018; Tan et al., Medicine 97(13):e0197, 2018; Reithdorf et al., Transl. Androl. Urol. 6(6):1090-1110, 2017; Volckmar et al., Genes Chromosomes Cancer 57(3):123-139, 2018; And Lu et al., Chronic Dis. Transl. Med. 2(4):223-230, 2016]. Additional methods of detecting circulating tumor DNA are known in the art.

(a) detecting dysregulation of the expression or activity or level of a BTK gene, BTK kinase, or any of these in a sample from a subject in need of treatment for BTK-associated cancer; And (b) administering to the subject a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. Also provided herein are methods of treating -associated cancer. In some embodiments, the method comprises the steps of (after (b)) (c) determining whether the cancer cells in a sample obtained from the subject have at least one BTK inhibitor resistance mutation; And (d) when the subject has cancer cells having at least one BTK inhibitor resistance mutation, the subject is given a compound of formula I of step (b), or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, spray- An additional dose of the dried dispersion or pharmaceutical composition thereof is administered as monotherapy or as another anticancer agent (e.g., a second BTK inhibitor, a second compound of formula I or a pharmaceutically acceptable salt thereof, in amorphous or polymorphic form, And a spray-dried dispersion thereof or a pharmaceutical composition thereof, or immunotherapy) or anticancer therapy (eg, surgery or radiation). In some embodiments, (a) detecting dysregulation of the expression or activity or level of a BTK gene, BTK kinase, or any of these in a sample from a subject in need of treatment of a BTK-associated cancer; And (b) administering to the subject a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. -Provided herein are methods of treating associated cancer. In some embodiments, the method comprises the steps of (after (b)) (c) determining whether the cancer cells in a sample obtained from the subject have at least one BTK inhibitor resistance mutation; And (d) when the subject has cancer cells having at least one BTK inhibitor resistance mutation, the subject is given a compound of formula I of step (b), or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, spray- An additional dose of the dried dispersion or pharmaceutical composition thereof is administered as monotherapy or as another anticancer agent (e.g., a second BTK inhibitor, a second compound of formula I or a pharmaceutically acceptable salt thereof, in amorphous or polymorphic form, And a spray-dried dispersion thereof or a pharmaceutical composition thereof, or immunotherapy) or anticancer therapy (eg, surgery or radiation). In some embodiments, (a) one or more BTK kinase protein point mutations/insertions of Table 1 in a sample from a subject in need of treatment of BTK-associated cancer, BTK fusion of Table 1a, p65BTK, BTK-C, or Detecting at least one BTK mutation selected from the group consisting of at least one BCR signaling pathway gene mutation in Table 4; And (b) to the subject a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, in amorphous or polymorphic form, a spray-dried dispersion thereof or a pharmaceutical composition thereof, or a pharmaceutical composition thereof. Provided herein are methods of treating BTK-associated cancer in a subject comprising administering a phase acceptable salt, amorphous or polymorphic form, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. In some embodiments, the method comprises the steps of (after (b)) (c) determining whether the cancer cells in the sample obtained from the subject have at least one BTK inhibitor resistance mutation in Table 2; And (d) when the subject has cancer cells having at least one BTK inhibitor resistance mutation, the subject is given a compound of formula I of step (b), or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, spray- An additional dose of the dried dispersion or pharmaceutical composition thereof is administered as monotherapy or as another anticancer agent (e.g., a second BTK inhibitor, a second compound of formula I or a pharmaceutically acceptable salt thereof, in amorphous or polymorphic form, And a spray-dried dispersion thereof or a pharmaceutical composition thereof, or immunotherapy) or anticancer therapy (eg, surgery or radiation). In some embodiments, Ibrutinib, PRN1008, PRN473, ABBV-105, AC0058, Acalabrutinib, Janubrutinib, Sfebrutinib, Porceltinib, Evobrutinib, Tiravlutinib, CG'806, ARQ 531 , BIIB068, Becabrutinib, AS871, CB1763, CB988, GDC-0853, RN486, GNE-504, GNE-309, BTK Max, Dasatinib, CT-1530, CGI-1746, CGI-560, LFM A13, TP A second BTK inhibitor selected from the group consisting of -0158, dtrmwxhs-12, CNX-774 and LOU064 is administered in step (d). In some embodiments, (a) detecting ^{MYD88 L265P} in a sample from a subject in need of treatment of a BTK-associated cancer; And (b) administering to the subject a therapeutically effective amount of a compound of Formula I-IV, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a method of treating BTK-associated cancer in a subject herein is disclosed herein. Is provided. In some embodiments, the method comprises (after (b)) (c) determining whether the cancer cells in the sample obtained from the subject have the BTK inhibitor resistance mutations C481S, C481F, C481T, C481G, C481R, T474I, T474M, or T474S. step; And (d) when the subject has cancer cells having at least one BTK inhibitor resistance mutation, the subject is given a compound of formula I of step (b), or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, spray- An additional dose of the dried dispersion or pharmaceutical composition thereof is administered as monotherapy or as another anticancer agent (e.g., a second BTK inhibitor, a second compound of formula I or a pharmaceutically acceptable salt thereof, in amorphous or polymorphic form, And a spray-dried dispersion thereof or a pharmaceutical composition thereof, or immunotherapy) or anticancer therapy (eg, surgery or radiation). In some embodiments, Ibrutinib, PRN1008, PRN473, ABBV-105, AC0058, Acalabrutinib, Janubrutinib, Sfebrutinib, Porceltinib, Evobrutinib, Tiravlutinib, CG'806, ARQ 531 , BIIB068, Becabrutinib, AS871, CB1763, CB988, GDC-0853, RN486, GNE-504, GNE-309, BTK Max, Dasatinib, CT-1530, CGI-1746, CGI-560, LFM A13, TP A second BTK inhibitor selected from the group consisting of -0158, dtrmwxhs-12, CNX-774 and LOU064 is administered in step (d).

(a) detecting dysregulation of the expression or activity or level of a BTK gene, BTK kinase, or any of these in a sample from a subject in need of treatment for BTK-associated cancer; And (b) administering to the subject a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. Also provided herein are methods of treating -associated cancer. In some embodiments, the method comprises (after (b)) (c) detecting at least one BTK inhibitor resistance mutation in cancer cells in a sample obtained from a subject; And (d) to the subject an additional dose of a compound of formula I of step (b) or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical composition thereof as monotherapy or or Other anticancer agents (e.g., a second BTK inhibitor, a second compound of formula I or a pharmaceutically acceptable salt thereof, in amorphous or polymorphic form, a spray-dried dispersion thereof or a pharmaceutical composition thereof, or an immunotherapy) or anticancer It further comprises administering in conjunction with therapy (eg, surgery or radiation). In some embodiments, (a) detecting dysregulation of the expression or activity or level of a BTK gene, BTK kinase, or any of them in a sample from a subject in need of treatment of a BTK-associated cancer; And (b) administering to the subject a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. -Provided herein are methods of treating associated cancer. In some embodiments, the method comprises (after (b)) (c) detecting at least one BTK inhibitor resistance mutation in cancer cells in a sample obtained from a subject; And (d) to the subject an additional dose of a compound of formula I of step (b) or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical composition thereof as monotherapy or or Other anticancer agents (e.g., a second BTK inhibitor, a second compound of formula I or a pharmaceutically acceptable salt thereof, in amorphous or polymorphic form, a spray-dried dispersion thereof or a pharmaceutical composition thereof, or an immunotherapy) or anticancer It further comprises administering in conjunction with therapy (eg, surgery or radiation). In some embodiments, (a) one or more BTK kinase protein point mutations/insertions of Table 1 in a sample from a subject in need of treatment of BTK-associated cancer, BTK fusion of Table 1a, p65BTK, BTK-C, or Detecting at least one BTK mutation selected from the group consisting of at least one BCR signaling pathway gene mutation in Table 4; And (b) to the subject a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, in amorphous or polymorphic form, a spray-dried dispersion thereof or a pharmaceutical composition thereof, or a pharmaceutical composition thereof. Provided herein are methods of treating BTK-associated cancer in a subject comprising administering a phase acceptable salt, amorphous or polymorphic form, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. In some embodiments, the method comprises the steps of (after (b)) (c) detecting at least one BTK inhibitor resistance mutation of Table 2 in cancer cells in a sample obtained from a subject; And (d) to the subject an additional dose of a compound of formula I of step (b) or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical composition thereof as monotherapy or or Other anticancer agents (e.g., a second BTK inhibitor, a second compound of formula I or a pharmaceutically acceptable salt thereof, in amorphous or polymorphic form, a spray-dried dispersion thereof or a pharmaceutical composition thereof, or an immunotherapy) or anticancer It further comprises administering in conjunction with therapy (eg, surgery or radiation). In some embodiments, Ibrutinib, PRN1008, PRN473, ABBV-105, AC0058, Acalabrutinib, Janubrutinib, Sfebrutinib, Porceltinib, Evobrutinib, Tiravlutinib, CG'806, ARQ 531 , BIIB068, Becabrutinib, AS871, CB1763, CB988, GDC-0853, RN486, GNE-504, GNE-309, BTK Max, Dasatinib, CT-1530, CGI-1746, CGI-560, LFM A13, TP A second BTK inhibitor selected from the group consisting of -0158, dtrmwxhs-12, CNX-774, LOU064 and combinations thereof is administered in step (d). In some embodiments, the method comprises ((b) after) (c) detecting a BTK inhibitor resistance mutation C481S, C481F, C481T, C481G, C481R, T474I, T474M, or T474S in cancer cells in a sample obtained from the subject; And (d) to the subject an additional dose of a compound of formula I of step (b) or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical composition thereof as monotherapy or or Other anticancer agents (e.g., a second BTK inhibitor, a second compound of formula I or a pharmaceutically acceptable salt thereof, in amorphous or polymorphic form, a spray-dried dispersion thereof or a pharmaceutical composition thereof, or an immunotherapy) or anticancer It further comprises administering in conjunction with therapy (eg, surgery or radiation). In some embodiments, Ibrutinib, PRN1008, PRN473, ABBV-105, AC0058, Acalabrutinib, Janubrutinib, Sfebrutinib, Porceltinib, Evobrutinib, Tiravlutinib, CG'806, ARQ 531 , BIIB068, Becabrutinib, AS871, CB1763, CB988, GDC-0853, RN486, GNE-504, GNE-309, BTK Max, Dasatinib, CT-1530, CGI-1746, CGI-560, LFM A13, TP A second BTK inhibitor selected from the group consisting of -0158, dtrmwxhs-12, CNX-774 and LOU064 is administered in step (d).

Identifying a subject having cancer cells with one or more BTK inhibitor resistance mutations; And selecting a treatment comprising administration of a compound of Formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical composition thereof. Methods of selecting treatment are also provided. In some embodiments, the one or more BTK inhibitor resistance mutations confer increased resistance to treatment with the first BTK inhibitor to the cancer cell or tumor. In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof is administered in combination with a first BTK inhibitor. Of a compound of formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form, spray-dried dispersion thereof, or a pharmaceutical composition thereof, for a subject identified as having cancer cells with one or more BTK inhibitor resistance mutations Also provided is a method of selecting a treatment for a subject having cancer comprising selecting a treatment comprising administration. Identifying a subject having cancer cells with one or more BTK inhibitor resistance mutations; And selecting an identified subject for treatment comprising a compound of Formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical composition thereof, as a monotherapy. Also provided is a method of selecting a subject with cancer for treatment that does not include the first BTK inhibitor. Cancer cells having one or more BTK inhibitor resistance mutations for treatment comprising administration of a compound of formula (I) or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical composition thereof Also provided is a method of selecting a subject with cancer for treatment that does not include the first BTK inhibitor as monotherapy, comprising selecting a subject identified as having. In some embodiments, the one or more BTK inhibitor resistance mutations comprise one or more BTK inhibitor resistance mutations listed in Table 2. In some embodiments, the one or more BTK inhibitor resistance mutations replace a substitution at amino acid position 481, e.g., C481S, C481F, C481T, C481G and C481R, or a substitution at amino acid position 474, e.g. T474I, T474M and T474S. Can include. As another example, the one or more BTK inhibitor resistance mutations may comprise a substitution at amino acid positions 244, 257, 334, 495, 664, 665, 707, 708, 742, 845, 848, 993, 1140 or 1141 of PLCγ2. I can. In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof is an additional therapeutic agent that inhibits the upstream protein of BTK in the BCR signaling pathway. It is administered in combination with. In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof is an additional therapeutic agent that inhibits a protein downstream of BTK in the BCR signaling pathway. It is administered in combination with. In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof is an additional therapeutic agent that inhibits a protein downstream of BTK in the BCR signaling pathway. , E.g., in combination with a PLCy2 inhibitor, wherein one or more resistance mutations are within PLCy2 (e.g., amino acid positions 244, 257, 334, 495, 664, 665, 707, 708, 742, 845, 848, 993, 1140 or 1141).

Determining whether the cancer cells in the sample obtained from the subject having cancer (eg, BTK-associated cancer) have one or more BTK inhibitor resistance mutations; And determining whether a subject having cancer cells with one or more BTK inhibitor resistance mutations has a reduced likelihood of having a positive response to treatment with the first BTK inhibitor as monotherapy (i.e., an increased likelihood of having a negative response). Also provided is a method of determining the likelihood that a subject having cancer (eg, BTK-associated cancer), comprising the step, will have a positive reaction to treatment with a first BTK inhibitor as monotherapy. Determining whether the cancer cells in the sample obtained from the subject having cancer (eg, BTK-associated cancer) have one or more BTK inhibitor resistance mutations; And a subject who does not have cancer cells with one or more BTK inhibitor resistance mutations will have a positive response to treatment with a first BTK inhibitor as monotherapy compared to a subject with cancer cells with one or more BTK inhibitor resistance mutations. A method of determining the likelihood that a subject with cancer (e.g., BTK-associated cancer) will have a positive response to treatment with a first BTK inhibitor as monotherapy, comprising determining that it has an increased likelihood. Also provided. Determining whether the cancer cells in the sample obtained from the subject have at least one BTK inhibitor resistance mutation; And determining whether treatment with the first BTK inhibitor as monotherapy is less likely to be effective in a subject having cancer cells in a sample obtained from a subject having one or more BTK inhibitor resistance mutations. Also provided are methods of predicting the efficacy of treatment with a first BTK inhibitor as monotherapy in a subject. A subject with cancer comprising the step of determining whether treatment with a first BTK inhibitor as monotherapy is less likely to be effective in a subject having cancer cells in a sample obtained from a subject having one or more BTK inhibitor resistance mutations. Also provided is a method of predicting the efficacy of treatment with a first BTK inhibitor as a monotherapy in. In some embodiments, the one or more BTK inhibitor resistance mutations confer increased resistance to treatment with the first BTK inhibitor to the cancer cell or tumor. In some embodiments, the one or more BTK inhibitor resistance mutations comprise one or more BTK inhibitor resistance mutations listed in Table 2. For example, the one or more BTK inhibitor resistance mutations may have a substitution at amino acid position 804, e.g. V804M, V804L or V804E, or a substitution at amino acid position 810, e.g. G810S, G810R, G810C, G810A, G810V and G810D. It may include. As another example, the one or more BTK inhibitor resistance mutations may comprise a substitution at amino acid positions 244, 257, 334, 495, 664, 665, 707, 708, 742, 845, 848, 993, 1140 or 1141 of PLCγ2. I can.

(a) administering to a subject having cancer at least one dose of a first BTK inhibitor for a predetermined period of time; (b) after (a), determining whether the cancer cells in the sample obtained from the subject have at least one BTK inhibitor resistance mutation; And (c) when the subject has cancer cells with at least one BTK inhibitor resistance mutation, to the subject a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or Administering the pharmaceutical composition thereof as monotherapy or in combination with another anticancer agent; Or (d) if the subject has cancer cells that do not have a BTK inhibitor resistance mutation, administering to the subject an additional dose of the first BTK inhibitor of step (a). Methods are also provided. In some embodiments, when the subject is administered an additional dose of the first BTK inhibitor of step (a), the subject also has another anticancer agent (e.g., a second BTK inhibitor, or a compound of formula I or a pharmaceutically Phase acceptable salts, amorphous or polymorphic forms, spray-dried dispersions thereof or pharmaceutical compositions thereof, or immunotherapy) may be administered. In some embodiments, the additional anticancer agent is any anticancer agent known in the art. For example, the additional anticancer agent is another BTK inhibitor (eg, a second BTK inhibitor). In some embodiments, the additional anticancer agent is immunotherapy. In some embodiments of step (c), another BTK inhibitor may be the first BTK inhibitor administered in step (a). In some embodiments, the one or more BTK inhibitor resistance mutations confer increased resistance to treatment with the first BTK inhibitor to the cancer cell or tumor. In some embodiments, the one or more BTK inhibitor resistance mutations comprise one or more BTK inhibitor resistance mutations listed in Table 2. For example, the one or more BTK inhibitor resistance mutations may have a substitution at amino acid position 804, e.g. V804M, V804L or V804E, or a substitution at amino acid position 810, e.g. G810S, G810R, G810C, G810A, G810V and G810D. It may include. As another example, the one or more BTK inhibitor resistance mutations may comprise a substitution at amino acid positions 244, 257, 334, 495, 664, 665, 707, 708, 742, 845, 848, 993, 1140 or 1141 of PLCγ2. I can. In some embodiments, the additional anticancer agent inhibits a protein upstream of BTK in the BCR signaling pathway. In some embodiments, the additional anticancer agent inhibits a protein downstream of BTK in the BCR signaling pathway. In some embodiments, the additional anticancer agent is a PLCy2 inhibitor, wherein the one or more resistance mutations are within PLCy2 (e.g., amino acid positions 244, 257, 334, 495, 664, 665, 707, 708, 742, 845, 848 , 993, 1140 or 1141).

(a) administering to a subject having cancer at least one dose of a first BTK inhibitor for a predetermined period of time; (b) after (a), determining whether the cancer cells in the sample obtained from the subject have at least one BTK inhibitor resistance mutation; And (c) if the subject has cancer cells having at least one BTK inhibitor resistance mutation, administering to the subject a second BTK inhibitor as monotherapy or with another anticancer agent; Or (d) if the subject has cancer cells that do not have a BTK inhibitor resistance mutation, administering to the subject an additional dose of the first BTK inhibitor of step (a). Methods are also provided. In some embodiments, if the subject is administered an additional dose of the first BTK inhibitor of step (a), the subject may also be administered another anticancer agent. In some embodiments, the one or more BTK inhibitor resistance mutations confer increased resistance to treatment with the first BTK inhibitor to the cancer cell or tumor. In some embodiments, the one or more BTK inhibitor resistance mutations comprise one or more BTK inhibitor resistance mutations listed in Table 2. For example, the one or more BTK inhibitor resistance mutations may have a substitution at amino acid position 804, e.g. V804M, V804L or V804E, or a substitution at amino acid position 810, e.g. G810S, G810R, G810C, G810A, G810V and G810D. It may include. As another example, the one or more BTK inhibitor resistance mutations may comprise a substitution at amino acid positions 244, 257, 334, 495, 664, 665, 707, 708, 742, 845, 848, 993, 1140 or 1141 of PLCγ2. I can. In some embodiments, the additional anticancer agent is any anticancer agent known in the art. For example, the additional anticancer agent is another BTK inhibitor (eg, a compound of formula I or a pharmaceutically acceptable salt thereof, in amorphous or polymorphic form, a spray-dried dispersion thereof or a pharmaceutical composition thereof). In some embodiments, the additional anticancer agent is immunotherapy. In some embodiments, the additional anticancer agent inhibits a protein upstream of BTK in the BCR signaling pathway. In some embodiments, the additional anticancer agent inhibits a protein downstream of BTK in the BCR signaling pathway. In some embodiments, the additional anticancer agent is a PLCy2 inhibitor, wherein the one or more resistance mutations are within PLCy2 (e.g., amino acid positions 244, 257, 334, 495, 664, 665, 707, 708, 742, 845, 848 , 993, 1140 or 1141).

(a) determining whether cancer cells in a sample obtained from a subject having cancer and previously administered one or more doses of a first BTK inhibitor have one or more BTK inhibitor resistance mutations; And (b) when the subject has cancer cells with at least one BTK inhibitor resistance mutation, to the subject a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or Administering the pharmaceutical composition thereof as monotherapy or in combination with another anticancer agent; Or (c) if the subject has cancer cells that do not have a BTK inhibitor resistance mutation, comprising administering an additional dose of a first BTK inhibitor previously administered to the subject (e.g., BTK- Associated cancer) is also provided. In some embodiments, when the subject is administered an additional dose of a first BTK inhibitor previously administered to the subject, the subject is given another anticancer agent (e.g., a compound of Formula I or a pharmaceutically acceptable salt thereof, Or a polymorphic form, a spray-dried dispersion thereof or a pharmaceutical composition thereof, or immunotherapy) may also be administered. In some embodiments, the one or more BTK inhibitor resistance mutations confer increased resistance to treatment with the first BTK inhibitor to the cancer cell or tumor. In some embodiments, the one or more BTK inhibitor resistance mutations comprise one or more BTK inhibitor resistance mutations listed in Table 2. For example, the one or more BTK inhibitor resistance mutations may have a substitution at amino acid position 804, e.g. V804M, V804L or V804E, or a substitution at amino acid position 810, e.g. G810S, G810R, G810C, G810A, G810V and G810D. It may include. As another example, the one or more BTK inhibitor resistance mutations may comprise a substitution at amino acid positions 244, 257, 334, 495, 664, 665, 707, 708, 742, 845, 848, 993, 1140 or 1141 of PLCγ2. I can. In some embodiments, the additional anticancer agent is any anticancer agent known in the art. For example, the additional anticancer agent is another BTK inhibitor (eg, a second BTK inhibitor). In some embodiments, the additional anticancer agent is immunotherapy. In some embodiments of step (b), another anticancer agent may be the first BTK inhibitor administered in step (a). In some embodiments, the additional anticancer agent inhibits a protein upstream of BTK in the BCR signaling pathway. In some embodiments, the additional anticancer agent inhibits a protein downstream of BTK in the BCR signaling pathway. In some embodiments, the additional anticancer agent is a PLCy2 inhibitor, wherein the one or more resistance mutations are within PLCy2 (e.g., amino acid positions 244, 257, 334, 495, 664, 665, 707, 708, 742, 845, 848 , 993, 1140 or 1141).

(a) determining whether cancer cells in a sample obtained from a subject having cancer and previously administered one or more doses of a first BTK inhibitor have one or more BTK inhibitor resistance mutations; And (b) if the subject has cancer cells having at least one BTK inhibitor resistance mutation, administering to the subject a second BTK inhibitor as monotherapy or with another anticancer agent; Or (c) if the subject has cancer cells that do not have a BTK inhibitor resistance mutation, a method of treating a subject with cancer comprising administering an additional dose of a first BTK inhibitor previously administered to the subject. This is also provided. In some embodiments, if the subject is administered an additional dose of a first BTK inhibitor previously administered to the subject, the subject may also be administered another anticancer agent. In some embodiments, the one or more BTK inhibitor resistance mutations confer increased resistance to treatment with the first BTK inhibitor to the cancer cell or tumor. In some embodiments, the one or more BTK inhibitor resistance mutations comprise one or more BTK inhibitor resistance mutations listed in Table 2. For example, the one or more BTK inhibitor resistance mutations may have a substitution at amino acid position 804, e.g. V804M, V804L or V804E, or a substitution at amino acid position 810, e.g. G810S, G810R, G810C, G810A, G810V and G810D. It may include. As another example, the one or more BTK inhibitor resistance mutations may comprise a substitution at amino acid positions 244, 257, 334, 495, 664, 665, 707, 708, 742, 845, 848, 993, 1140 or 1141 of PLCγ2. I can. In some embodiments, the additional anticancer agent is any anticancer agent known in the art. For example, the additional anticancer agent is another BTK inhibitor (eg, a compound of formula I or a pharmaceutically acceptable salt thereof, in amorphous or polymorphic form, a spray-dried dispersion thereof or a pharmaceutical composition thereof). In some embodiments, the additional anticancer agent is immunotherapy. In some embodiments of (b), another anticancer agent may be the first BTK inhibitor administered in step (a). In some embodiments, the additional anticancer agent inhibits a protein upstream of BTK in the BCR signaling pathway. In some embodiments, the additional anticancer agent inhibits a protein downstream of BTK in the BCR signaling pathway. In some embodiments, the additional anticancer agent is a PLCy2 inhibitor, wherein the one or more resistance mutations are within PLCy2 (e.g., amino acid positions 244, 257, 334, 495, 664, 665, 707, 708, 742, 845, 848 , 993, 1140 or 1141).

In some embodiments, a BTK-associated cancer described herein can occur in a subject with dysregulation of the expression or activity or level of another gene, another protein, or any of these.

For example, a BTK-associated cancer exhibiting dysregulation of the expression or activity or level of the BTK gene, the BTK protein, or any of these, is the expression or activity of the BCR signaling pathway gene, the BCR signaling pathway protein, or any of these. Or dysregulation of the level (eg, amplification of the BCR signaling gene), or dysregulation of the expression or activity or level of the MYC gene, MYC protein, or any of these (eg, amplification of the MYC gene) 1 It can occur in a subject with species abnormalities.

In some embodiments, the methods described herein may further comprise detecting dysregulation of the expression or activity or level of the MYC gene, MYC protein, or any of them (e.g., amplification of the MYC gene). . In some embodiments, the method may further comprise administering an inhibitor of MYC.

Exemplary inhibitors of MYC include 10058-F4, 10074-G5 and KSI-3716.

In some embodiments, the BTK-associated cancer that exhibits dysregulation of the expression or activity or level of the MYC gene, MYC protein, or any of them (eg, amplification of the MYC gene) is esophageal cancer (eg, literature [ Chong et al., Gut. pii: gutjnl-2017-314408, 2017).

(a) administering to a subject having cancer at least one dose of a first BTK inhibitor for a predetermined period of time; (b) after (a), determining whether the cancer cells in the sample obtained from the subject have at least one BTK inhibitor resistance mutation; And (c) a compound of formula I for the subject, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof for the subject, when the subject has cancer cells with one or more BTK inhibitor resistance mutations. Or selecting a pharmaceutical composition thereof as monotherapy or in combination with another anticancer agent; Or (d) if the subject has cancer cells that do not have a BTK inhibitor resistance mutation, selecting an additional dose of the first BTK inhibitor of step (a) for the subject. Methods of selecting treatment are also provided. In some embodiments, if an additional dose of the first BTK inhibitor of step (a) is selected for the subject, the method may further comprise selecting a dose of another anticancer agent for the subject. In some embodiments, the one or more BTK inhibitor resistance mutations confer increased resistance to treatment with the first BTK inhibitor to the cancer cell or tumor. In some embodiments, the one or more BTK inhibitor resistance mutations comprise one or more BTK inhibitor resistance mutations listed in Table 2. For example, the one or more BTK inhibitor resistance mutations include a substitution at amino acid position 481, e.g. C481S, C481F, C481T, C481G or C481R, or a substitution at amino acid position 474, e.g. T474I, T474M or T474S. can do. As another example, the one or more BTK inhibitor resistance mutations may comprise a substitution at amino acid positions 244, 257, 334, 495, 664, 665, 707, 708, 742, 845, 848, 993, 1140 or 1141 of PLCγ2. I can. In some embodiments, the additional anticancer agent is any anticancer agent known in the art. For example, the additional anticancer agent is another BTK inhibitor (eg, a second BTK inhibitor). In some embodiments, the additional anticancer agent is immunotherapy. In some embodiments of step (c), another BTK inhibitor may be the first BTK inhibitor administered in step (a). In some embodiments, the additional anticancer agent inhibits a protein upstream of BTK in the BCR signaling pathway. In some embodiments, the additional anticancer agent inhibits a protein downstream of BTK in the BCR signaling pathway. In some embodiments, the additional anticancer agent is a PLCy2 inhibitor, wherein the one or more resistance mutations are within PLCy2 (e.g., amino acid positions 244, 257, 334, 495, 664, 665, 707, 708, 742, 845, 848 , 993, 1140 or 1141).

(a) administering to a subject having cancer at least one dose of a first BTK inhibitor for a predetermined period of time; (b) after (a), determining whether the cancer cells in the sample obtained from the subject have at least one BTK inhibitor resistance mutation; And (c) if the subject has cancer cells having one or more BTK inhibitor resistance mutations, selecting a second BTK inhibitor as monotherapy or in combination with another anticancer agent; Or (d) if the subject has cancer cells that do not have a BTK inhibitor resistance mutation, selecting an additional dose of the first BTK inhibitor of step (a) for the subject. Methods of selecting treatment are also provided. In some embodiments, if an additional dose of the first BTK inhibitor of step (a) is selected for the subject, the method may further comprise selecting a dose of another anticancer agent for the subject. In some embodiments, the one or more BTK inhibitor resistance mutations confer increased resistance to treatment with the first BTK inhibitor to the cancer cell or tumor. In some embodiments, the one or more BTK inhibitor resistance mutations comprise one or more BTK inhibitor resistance mutations listed in Table 2. For example, the one or more BTK inhibitor resistance mutations include a substitution at amino acid position 481, e.g., C481S, C481F, C481T, C481G, C481R, or a substitution at amino acid position 474, e.g. T474I, T474M or T474S. can do. As another example, the one or more BTK inhibitor resistance mutations may comprise a substitution at amino acid positions 244, 257, 334, 495, 664, 665, 707, 708, 742, 845, 848, 993, 1140 or 1141 of PLCγ2. I can. In some embodiments, the additional anticancer agent is any anticancer agent known in the art. For example, the additional anticancer agent is another BTK inhibitor (eg, a compound of formula I or a pharmaceutically acceptable salt thereof, in amorphous or polymorphic form, a spray-dried dispersion thereof or a pharmaceutical composition thereof). In some embodiments, the additional anticancer agent is immunotherapy. In some embodiments, another BTK inhibitor may be the first BTK inhibitor administered in step (a). In some embodiments, the additional anticancer agent inhibits a protein upstream of BTK in the BCR signaling pathway. In some embodiments, the additional anticancer agent inhibits a protein downstream of BTK in the BCR signaling pathway. In some embodiments, the additional anticancer agent is a PLCy2 inhibitor, wherein the one or more resistance mutations are within PLCy2 (e.g., amino acid positions 244, 257, 334, 495, 664, 665, 707, 708, 742, 845, 848 , 993, 1140 or 1141).

(a) determining whether cancer cells in a sample obtained from a subject having cancer and previously administered one or more doses of a first BTK inhibitor have one or more BTK inhibitor resistance mutations; (b) when the subject has cancer cells with at least one BTK inhibitor resistance mutation, a compound of formula I for the subject, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or Selecting a pharmaceutical composition thereof as monotherapy or in combination with another anticancer agent; Or (c) if the subject has cancer cells that do not have a BTK inhibitor resistance mutation, selecting an additional dose of the first BTK inhibitor previously administered to the subject. A method of selection is also provided. In some embodiments, when an additional dose of the first BTK inhibitor previously administered to the subject is selected for the subject, the method is another anticancer agent for the subject (e.g., a compound of formula I or a pharmaceutically acceptable It may further comprise the step of selecting the dose of the salt, amorphous or polymorphic form, a spray-dried dispersion thereof or a pharmaceutical composition thereof, or immunotherapy). In some embodiments, the one or more BTK inhibitor resistance mutations confer increased resistance to treatment with the first BTK inhibitor to the cancer cell or tumor. In some embodiments, the one or more BTK inhibitor resistance mutations comprise one or more BTK inhibitor resistance mutations listed in Table 2. For example, the one or more BTK inhibitor resistance mutations include a substitution at amino acid position 481, e.g., C481S, C481F, C481T, C481G, C481R, or a substitution at amino acid position 474, e.g. T474I, T474M or T474S. can do. As another example, the one or more BTK inhibitor resistance mutations may comprise a substitution at amino acid positions 244, 257, 334, 495, 664, 665, 707, 708, 742, 845, 848, 993, 1140 or 1141 of PLCγ2. I can. In some embodiments, the additional anticancer agent is any anticancer agent known in the art. For example, the additional anticancer agent is another BTK inhibitor (eg, a second BTK inhibitor). In some embodiments, the additional anticancer agent is immunotherapy. In some embodiments of step (c), another BTK inhibitor may be the first BTK inhibitor administered in step (a). In some embodiments, the additional anticancer agent inhibits a protein upstream of BTK in the BCR signaling pathway. In some embodiments, the additional anticancer agent inhibits a protein downstream of BTK in the BCR signaling pathway. In some embodiments, the additional anticancer agent is a PLCy2 inhibitor, wherein the one or more resistance mutations are within PLCy2 (e.g., amino acid positions 244, 257, 334, 495, 664, 665, 707, 708, 742, 845, 848 , 993, 1140 or 1141).

(a) determining whether cancer cells in a sample obtained from a subject having cancer and previously administered one or more doses of a first BTK inhibitor have one or more BTK inhibitor resistance mutations; (b) if the subject has cancer cells with at least one BTK inhibitor resistance mutation, selecting a second BTK inhibitor for the subject as monotherapy or in combination with another anticancer agent; Or (c) if the subject has cancer cells that do not have a BTK inhibitor resistance mutation, selecting an additional dose of the first BTK inhibitor previously administered to the subject. A method of selection is also provided. In some embodiments, when an additional dose of the first BTK inhibitor previously administered to the subject is selected for the subject, the method is another anticancer agent for the subject (e.g., a compound of formula I or a pharmaceutically acceptable It may further comprise the step of selecting the dose of the salt, amorphous or polymorphic form, a spray-dried dispersion thereof or a pharmaceutical composition thereof, or immunotherapy). In some embodiments, the one or more BTK inhibitor resistance mutations confer increased resistance to treatment with the first BTK inhibitor to the cancer cell or tumor. In some embodiments, the one or more BTK inhibitor resistance mutations comprise one or more BTK inhibitor resistance mutations listed in Table 2. For example, the one or more BTK inhibitor resistance mutations include a substitution at amino acid position 481, e.g., C481S, C481F, C481T, C481G, C481R, or a substitution at amino acid position 474, e.g. T474I, T474M or T474S. can do. As another example, the one or more BTK inhibitor resistance mutations may comprise a substitution at amino acid positions 244, 257, 334, 495, 664, 665, 707, 708, 742, 845, 848, 993, 1140 or 1141 of PLCγ2. I can. In some embodiments, the additional anticancer agent is any anticancer agent known in the art. For example, the additional anticancer agent is another BTK inhibitor (eg, a compound of formula I or a pharmaceutically acceptable salt thereof, in amorphous or polymorphic form, a spray-dried dispersion thereof or a pharmaceutical composition thereof). In some embodiments, the additional anticancer agent is immunotherapy. In some embodiments, another BTK can be the first BTK inhibitor administered in step (a). In some embodiments, the additional anticancer agent inhibits a protein upstream of BTK in the BCR signaling pathway. In some embodiments, the additional anticancer agent inhibits a protein downstream of BTK in the BCR signaling pathway. In some embodiments, the additional anticancer agent is a PLCy2 inhibitor, wherein the one or more resistance mutations are within PLCy2 (e.g., amino acid positions 244, 257, 334, 495, 664, 665, 707, 708, 742, 845, 848 , 993, 1140 or 1141).

Determining whether the cells in the sample obtained from the subject have one or more BTK inhibitor resistance mutations; And identifying a subject having cells with one or more BTK inhibitor resistance mutations as having an increased likelihood of developing a cancer with some resistance to the first BTK inhibitor. Also provided is a method of determining a subject's risk of developing cancer having cancer. Some resistance to a first BTK inhibitor comprising the step of identifying a subject having cells with at least one BTK inhibitor resistance mutation as having an increased likelihood of developing a cancer with some resistance to the first BTK inhibitor Also provided is a method of determining a subject's risk of developing a cancer having cancer. Determining whether the cancer cells in the sample obtained from the subject have at least one BTK inhibitor resistance mutation; And determining that a subject having cancer cells having one or more BTK inhibitor resistance mutations has a cancer having some resistance to the first BTK inhibitor. Also provided is a method of determining. A cancer having some resistance to a first BTK inhibitor, comprising the step of determining that a subject having cancer cells having one or more BTK inhibitor resistance mutations has a cancer having some resistance to the first BTK inhibitor. A method of determining existence is also provided. In some embodiments, the one or more BTK inhibitor resistance mutations confer increased resistance to treatment with the first BTK inhibitor to the cancer cell or tumor. In some embodiments, the one or more BTK inhibitor resistance mutations comprise one or more BTK inhibitor resistance mutations listed in Table 2. For example, the one or more BTK inhibitor resistance mutations include a substitution at amino acid position 481, e.g., C481S, C481F, C481T, C481G, C481R, or a substitution at amino acid position 474, e.g. T474I, T474M or T474S. can do. As another example, the one or more BTK inhibitor resistance mutations may comprise a substitution at amino acid positions 244, 257, 334, 495, 664, 665, 707, 708, 742, 845, 848, 993, 1140 or 1141 of PLCγ2. I can.

In some embodiments of any of the methods described herein, the BTK inhibitor resistance mutation that confers increased resistance to treatment with the first BTK inhibitor to the cancer cell or tumor is any BTK inhibitor resistance mutation listed in Table 3 or 4 (E.g., a substitution at amino acid position 481, for example C481S, C481F, C481T, C481G, C481R, or a substitution at amino acid position 474, such as T474I, T474M or T474S). As another example, the one or more BTK inhibitor resistance mutations may comprise a substitution at amino acid positions 244, 257, 334, 495, 664, 665, 707, 708, 742, 845, 848, 993, 1140 or 1141 of PLCγ2. I can.

In some embodiments, the presence of one or more BTK inhibitor resistance mutations in the tumor means that the tumor is using a compound of Formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form, spray-dried dispersion thereof, or a pharmaceutical composition thereof. Makes you more resistant to treatment. A method useful when the BTK inhibitor resistance mutation makes the tumor more resistant to treatment with a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical composition thereof. Are described below. For example, identifying a subject having cancer cells with one or more BTK inhibitor resistance mutations; And treatment not comprising a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical composition thereof as monotherapy to the identified subject (e.g., 2nd BTK Provided herein is a method of treating a subject having cancer comprising administering a kinase inhibitor). A compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical composition thereof as monotherapy to a subject identified as having cancer cells with one or more BTK inhibitor resistance mutations Also provided is a method of treating the subject comprising administering a treatment that does not include (eg, a second BTK kinase inhibitor). In some embodiments, the one or more BTK inhibitor resistance mutations are increased resistance to treatment with a compound of Formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. Is given to cancer cells or tumors.

Identifying a subject having cancer cells with one or more BTK inhibitor resistance mutations; And a treatment not comprising a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical composition thereof as monotherapy for an identified subject (e.g., a second BTK kinase inhibitors) are also provided herein. A compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical thereof as a monotherapy for a subject identified as having cancer cells with one or more BTK inhibitor resistance mutations Also provided is a method of selecting a treatment for a subject having cancer comprising selecting a treatment that does not include the composition (eg, a second BTK kinase inhibitor). Identifying a subject having cancer cells with one or more BTK inhibitor resistance mutations; And treatment not comprising a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical composition thereof as monotherapy (e.g., a second BTK kinase inhibitor). Treatment that does not include a compound of formula I or a pharmaceutically acceptable salt thereof, amorphous or polymorphic form, spray-dried dispersion thereof or a pharmaceutical composition thereof as monotherapy, comprising the step of selecting an identified subject for treatment ( For example, a method of selecting a subject with cancer for a second BTK kinase inhibitor) is also provided. Cancer cells having one or more BTK inhibitor resistance mutations for treatment not comprising a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical composition thereof as monotherapy A compound of formula I or a pharmaceutically acceptable salt thereof, amorphous or polymorphic form, a spray-dried dispersion thereof, or a pharmaceutical composition thereof as monotherapy, comprising the step of selecting a subject identified as having Also provided is a method of selecting a subject with cancer for treatment (eg, a second BTK kinase inhibitor). In some embodiments, the one or more BTK inhibitor resistance mutations are increased resistance to treatment with a compound of Formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. Is given to cancer cells or tumors.

Determining whether the cancer cells in the sample obtained from the subject with cancer have at least one BTK inhibitor resistance mutation; And a subject having cancer cells with one or more BTK inhibitor resistance mutations using a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof as monotherapy. A compound of formula (I) or a pharmaceutically acceptable salt thereof, amorphous or polymorphic form thereof, spray-drying thereof, comprising the step of determining that a subject with cancer has a reduced likelihood of having a positive response to treatment, as monotherapy. Also provided is a method of determining the likelihood of having a positive reaction to treatment with a modified dispersion or pharmaceutical composition thereof. Treatment of a subject having cancer cells with one or more BTK inhibitor resistance mutations as monotherapy with a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical composition thereof A subject having cancer, comprising the step of determining that it has a reduced likelihood of having a positive reaction for, is a compound of formula I as monotherapy, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, spray-dried thereof. Also provided is a method of determining the likelihood of having a positive reaction to treatment with a dispersion or a pharmaceutical composition thereof. Determining whether the cancer cells in the sample obtained from the subject have at least one BTK inhibitor resistance mutation; And treatment with a compound of formula (I) or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical composition thereof as monotherapy obtained from a subject having at least one BTK inhibitor resistance mutation. A compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray thereof as monotherapy in a subject with cancer, comprising determining whether it is less likely to be effective in a subject with cancer cells in the sample. -A method of predicting the efficacy of a treatment with a dried dispersion or pharmaceutical composition thereof is also provided. A sample obtained from a subject having at least one BTK inhibitor resistance mutation for treatment with a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical composition thereof as monotherapy A compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray thereof as monotherapy in a subject with cancer, comprising the step of determining whether it is less likely to be effective in a subject having cancer cells within Also provided is a method of predicting the efficacy of a treatment with a dried dispersion or pharmaceutical composition thereof. In some embodiments, the one or more BTK inhibitor resistance mutations are increased resistance to treatment with a compound of Formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. Is given to cancer cells or tumors.

(a) administering one or more doses of a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof for a predetermined period of time; (b) after (a), determining whether the cancer cells in the sample obtained from the subject have one or more BTK inhibitor resistance mutations; And (c) a second BTK inhibitor or a second compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof to a subject having cancer cells with at least one BTK inhibitor resistance mutation. Administering water or a pharmaceutical composition thereof as monotherapy or in combination with another anticancer agent; Or (d) a compound of formula I of step (a) or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical thereof to a subject having cancer cells without a BTK inhibitor resistance mutation. Also provided is a method of treating a subject having cancer comprising administering an additional dose of the composition. In some embodiments, when the subject is administered an additional dose of a compound of formula I of step (a), or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. , The subject may also be administered another anticancer agent or a second compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical composition thereof. In some embodiments, the one or more BTK inhibitor resistance mutations are increased resistance to treatment with a compound of Formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. Is given to cancer cells or tumors. In some embodiments, the additional anticancer agent is any anticancer agent known in the art. For example, the additional anticancer agent is another BTK inhibitor (eg, a second BTK inhibitor). In some embodiments, the additional anticancer agent is immunotherapy. In some embodiments, another BTK may be a compound of Formula I administered in step (a), or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof.

(a) obtained from a subject having cancer and previously administered one or more doses of a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. Determining whether the cancer cells in the sample have one or more BTK inhibitor resistance mutations; (b) a second BTK inhibitor or a second compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof to a subject having cancer cells with one or more BTK inhibitor resistance mutations. Or administering the pharmaceutical composition thereof as monotherapy or in combination with another anticancer agent; Or (c) a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical composition thereof, previously administered to a subject having cancer cells that do not have a BTK inhibitor resistance mutation. Also provided is a method of treating a subject having cancer comprising administering an additional dose of. In some embodiments, when the subject is administered an additional dose of a compound of formula I of step (a), or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. , The subject can also be administered another anticancer agent. In some embodiments, the one or more BTK inhibitor resistance mutations are increased resistance to treatment with a compound of Formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. Is given to cancer cells or tumors. In some embodiments, the additional anticancer agent is any anticancer agent known in the art. For example, the additional anticancer agent is another BTK inhibitor (eg, a second BTK inhibitor). In some embodiments, the additional anticancer agent is immunotherapy. In some embodiments, another BTK may be a compound of Formula I administered in step (a), or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof.

(a) administering to a subject having cancer at least one dose of a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof for a predetermined period of time; (b) after (a), determining whether the cancer cells in the sample obtained from the subject have one or more BTK inhibitor resistance mutations; And (c) when the subject has cancer cells having a BTK inhibitor resistance mutation, a second BTK inhibitor for the subject or a second compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, spray thereof- Selecting the dried dispersion or a pharmaceutical composition thereof as monotherapy or in combination with another anticancer agent; Or (d) when the subject has cancer cells that do not have a BTK inhibitor resistance mutation, the compound of formula I of step (a) for the subject, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, spray-dried thereof Also provided is a method of selecting a treatment for a subject having cancer comprising selecting an additional dose of the prepared dispersion or pharmaceutical composition thereof. In some embodiments, when an additional dose of the compound of formula I in step (a) or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical composition thereof is selected for the subject. Eh, the method may also further comprise the step of selecting another anticancer agent. In some embodiments, the one or more BTK inhibitor resistance mutations are increased resistance to treatment with a compound of Formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. Is given to cancer cells or tumors. In some embodiments, the additional anticancer agent is any anticancer agent known in the art. For example, the additional anticancer agent is another BTK inhibitor (eg, a second BTK inhibitor). In some embodiments, the additional anticancer agent is immunotherapy. In some embodiments, another BTK may be a compound of Formula I administered in step (a), or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof.

(a) obtained from a subject having cancer and previously administered one or more doses of a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. Determining whether the cancer cells in the sample have one or more BTK inhibitor resistance mutations; (b) a second BTK inhibitor for the subject or a second compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, spray-dried thereof for the subject when the subject has cancer cells with a BTK inhibitor resistance mutation Selecting the dispersion or a pharmaceutical composition thereof as monotherapy or in combination with another anticancer agent; Or (c) a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, previously administered to the subject when the subject has cancer cells that do not have a BTK inhibitor resistance mutation, a spray-dried dispersion thereof. Or a method of selecting a treatment for a subject having cancer comprising selecting an additional dose of a pharmaceutical composition thereof is also provided. In some embodiments, when an additional dose of the compound of formula I in step (a) or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical composition thereof is selected for the subject. Eh, the method may also further comprise the step of selecting another anticancer agent. In some embodiments, the one or more BTK inhibitor resistance mutations are increased resistance to treatment with a compound of Formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. Is given to cancer cells or tumors. In some embodiments, the additional anticancer agent is any anticancer agent known in the art. For example, the additional anticancer agent is another BTK inhibitor (eg, a second BTK inhibitor). In some embodiments, the additional anticancer agent is immunotherapy. In some embodiments, another BTK may be a compound of Formula I administered in step (a), or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof.

Determining whether the cells in the sample obtained from the subject have one or more BTK inhibitor resistance mutations; And when the subject has cells with one or more BTK inhibitor resistance mutations, the subject is added to a compound of formula (I) or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical composition thereof. A compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical composition thereof, comprising the step of identifying as having an increased likelihood of developing cancer with some resistance to cancer. Also provided are methods of determining a subject's risk of developing cancer with some resistance to. Subjects having cells with one or more BTK inhibitor resistance mutations have some resistance to a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. Some resistance to a compound of formula (I), or a pharmaceutically acceptable salt, amorphous or polymorphic form, spray-dried dispersion thereof, or a pharmaceutical composition thereof, comprising the step of identifying as having an increased likelihood of developing cancer. Also provided is a method of determining a subject's risk of developing a cancer having cancer. Determining whether the cancer cells in the sample obtained from the subject have at least one BTK inhibitor resistance mutation; And a subject having cancer cells having at least one BTK inhibitor resistance mutation has some resistance to a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. Presence of cancer having some resistance to a compound of formula (I) or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical composition thereof, comprising the step of determining to have a cancer having Also provided is a method of determining. A subject having cancer cells having one or more BTK inhibitor resistance mutations has some resistance to a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. Of cancer having some resistance to a compound of formula (I) or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof, in a subject comprising the step of determining to have cancer. A method of determining existence is also provided. In some embodiments, the one or more BTK inhibitor resistance mutations are increased resistance to treatment with a compound of Formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. Is given to cancer cells or tumors.

In some embodiments of any of the methods described herein, increased resistance to treatment with a compound of Formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof is achieved. The BTK inhibitor resistance mutation imparted to cancer cells or tumors may be any of the BTK inhibitor resistance mutations listed in Table 2. Methods of determining the level of resistance of a cancer cell or tumor to a BTK inhibitor (eg, any BTK inhibitor described herein or known in the art) can be determined using methods known in the art. For example, the level of resistance of a cancer cell to a BTK inhibitor can be assessed by determining _{the IC 50} of a BTK inhibitor (e.g., any BTK inhibitor described herein or known in the art) on the survival rate of the cancer cell. I can. In another example, the level of resistance of a cancer cell to a BTK inhibitor can be assessed by determining the growth rate of a cancer cell in the presence of a BTK inhibitor (eg, any BTK inhibitor described herein). In another example, the level of resistance of a tumor to a BTK inhibitor is determined by determining the mass or size of one or more tumors in a subject over time during treatment with a BTK inhibitor (e.g., any BTK inhibitor described herein). Can be evaluated. In another example, the level of resistance of a cancer cell or tumor to a BTK inhibitor is determined by determining the activity of a BTK kinase comprising one or more of the BTK inhibitor resistance mutations (i.e., the same BTK kinase expressed in a cancer cell or tumor in a subject). It can be evaluated indirectly. The level of resistance of cancer cells or tumors having one or more BTK inhibitor resistance mutations to the BTK inhibitor is a cancer cell or tumor that does not have the BTK inhibitor resistance mutation (e.g., cancer cells or tumors that do not have the same BTK inhibitor resistance mutation, Cancer cells or tumors that do not have any BTK inhibitor resistance mutations, or cancer cells or tumors expressing the wild-type BTK protein). For example, the determined resistance level of a cancer cell or tumor having one or more BTK inhibitor resistance mutations is a cancer cell or tumor that does not have the BTK inhibitor resistance mutation (e.g., a cancer cell or tumor that does not have the same BTK inhibitor resistance mutation). , Greater than about 1%, greater than about 2%, greater than about 3%, greater than about 4% of the level of resistance in cancer cells or tumors that do not have any BTK inhibitor resistance mutations, or cancer cells or tumors expressing wild-type BTK protein). , Greater than about 5%, greater than about 6%, greater than about 7%, greater than about 8%, greater than about 9%, greater than about 10%, greater than about 11%, greater than about 12%, greater than about 13%, greater than about 14% , Greater than about 15%, greater than about 20%, greater than about 25%, greater than about 30%, greater than about 35%, greater than about 40%, greater than about 45%, greater than about 50%, greater than about 60%, greater than about 70% , Greater than about 80%, greater than about 90%, greater than about 100%, greater than about 110%, greater than about 120%, greater than about 130%, greater than about 140%, greater than about 150%, greater than about 160%, greater than about 170% , Greater than about 180%, greater than about 190%, greater than about 200%, greater than about 210%, greater than about 220%, greater than about 230%, greater than about 240%, greater than about 250%, greater than about 260%, greater than about 270% , Greater than about 280%, greater than about 290%, or greater than about 300%.

A subject having cancer (eg, any cancer described herein) and/or (i) the cancer in the subject relapsed during therapy with the first BTK inhibitor; (ii) the cancer in the subject is not responding to therapy with the first BTK inhibitor and/or; (iii) A treatment that does not include a first BTK inhibitor (e.g., a first BTK inhibitor such as ibrutinib or acalabrutinib) as monotherapy to such a subject that the subject is intolerant to the first BTK inhibitor (e.g. Also provided herein is a method of treating a subject comprising administering, for example, any treatment that does not include a first BTK inhibitor) as the monotherapy described herein. For example, a second BTK inhibitor can be administered to the subject as monotherapy or in combination with another anticancer agent or treatment (eg, a first BTK inhibitor).

(i) the cancer in the subject has relapsed during therapy with the first BTK inhibitor and/or; (ii) the cancer in the subject is not responding to therapy with the first BTK inhibitor and/or; (iii) a method of treating a subject comprising administering to a subject having a clinical record indicating that the subject is intolerant to the first BTK inhibitor, as monotherapy, a therapeutically effective amount of a treatment not comprising the first BTK inhibitor is also provided. Provided herein. For example, a second BTK inhibitor can be administered to the subject as monotherapy or in combination with another anticancer agent or treatment (eg, a first BTK inhibitor).

(i) the cancer in the subject has relapsed during therapy with the first BTK inhibitor and/or; (ii) the cancer in the subject is not responding to therapy with the first BTK inhibitor and/or; (iii) identifying such a subject that the subject is intolerant to the first BTK inhibitor; And administering to the identified subject a treatment comprising a compound of formula (I) or a pharmaceutically acceptable salt, amorphous or polymorphic form, a spray-dried dispersion thereof, or a pharmaceutical composition thereof, to the identified subject. For example, methods of treating a subject with any cancer described herein or known in the art are also provided herein.

(i) the cancer in the subject has relapsed during therapy with the first BTK inhibitor and/or; (ii) the cancer in the subject is not responding to therapy with the first BTK inhibitor and/or; (iii) identifying such a subject that the subject is intolerant to the first BTK inhibitor; And to the identified subject a compound of formula (I) or a pharmaceutically acceptable salt thereof, amorphous or polymorphic form, a spray-dried dispersion thereof or a pharmaceutical composition thereof and another anticancer agent (e.g., any one of the anticancer agents described herein Cancer (e.g., described herein or known in the art), comprising administering a treatment comprising a species or more) or an anti-cancer therapy (e.g., any one or more of the anti-cancer therapies provided herein). Any cancer) is also provided herein.

A subject identified as having cancer and (i) the cancer in the subject relapsed during therapy with the first BTK inhibitor and/or; (ii) the cancer in the subject is not responding to therapy with the first BTK inhibitor and/or; (iii) treatment comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, amorphous or polymorphic form, a spray-dried dispersion thereof or a pharmaceutical composition thereof to such a subject that the subject is intolerant to a first BTK inhibitor. Also provided herein is a method of treating the subject comprising administering.

A subject identified as having cancer and (i) the cancer in the subject relapsed during therapy with the first BTK inhibitor and/or; (ii) the cancer in the subject is not responding to therapy with the first BTK inhibitor and/or; (iii) A compound of formula (I) or a pharmaceutically acceptable salt thereof, amorphous or polymorphic form, a spray-dried dispersion thereof or a pharmaceutical composition thereof and another anticancer agent ( For example, the subject comprising administering a treatment comprising any one or more of the other anti-cancer agents described herein) or an anti-cancer therapy (e.g., any one or more of the anti-cancer therapies described herein). Methods of treatment are also provided herein.

(i) the cancer in the subject has relapsed during therapy with the first BTK inhibitor and/or; (ii) the cancer in the subject is not responding to therapy with the first BTK inhibitor and/or; (iii) A compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof, to a subject having a clinical record indicating that the subject is intolerant to the first BTK inhibitor. Also provided herein is a method of treating a subject having cancer comprising administering a therapeutically effective amount of a treatment comprising.

(i) the cancer in the subject has relapsed during therapy with the first BTK inhibitor and/or; (ii) the cancer in the subject is not responding to therapy with the first BTK inhibitor and/or; (iii) a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof, to a subject having a clinical record indicating that the subject is intolerant to the first BTK inhibitor, and Administering a therapeutically effective amount of a treatment comprising another anticancer agent (e.g., any one or more of the anticancer agents described herein) or an anticancer therapy (e.g., any one or more of the anticancer therapies described herein). Also provided herein are methods of treating a subject.

(a) administering to a subject having cancer at least one dose of a first BTK inhibitor for a predetermined period of time; (b) after (a), (i) the cancer in the subject relapsed during therapy with the first BTK inhibitor and/or; (ii) the cancer in the subject is not responding to therapy with the first BTK inhibitor and/or; (iii) determining whether the subject is intolerant to the first BTK inhibitor; And (c) (i) the cancer in the subject recurred during therapy with the first BTK inhibitor; (ii) the cancer in the subject is not responding to therapy with the first BTK inhibitor and/or; (iii) administering a treatment that does not include the BTK inhibitor of step (a) or a second BTK inhibitor as monotherapy to such a subject that the subject is intolerant to the first BTK inhibitor; Or (d) (i) the cancer in the subject recurred during therapy with the first BTK inhibitor; (ii) the cancer in the subject is not responding to therapy with the first BTK inhibitor and/or; (iii) Also provided herein is a method of treating a subject having cancer comprising administering to such subject the subject is intolerant to the first BTK inhibitor an additional dose of the first BTK inhibitor. In some embodiments, the second BTK inhibitor is a compound of Formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. In some embodiments, the second BTK inhibitor comprises a blending agent as disclosed herein and a compound of Formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. It is a pharmaceutical composition. In some embodiments, the cancer is a BTK-associated cancer.

(a) (i) the cancer in the subject having the cancer recurred during therapy with the first BTK inhibitor and/or; (ii) the cancer in the subject is not responding to therapy with the first BTK inhibitor and/or; (iii) determining whether the subject is intolerant to the first BTK inhibitor; And (b) (i) the cancer in the subject recurred during therapy with the first BTK inhibitor; (ii) the cancer in the subject is not responding to therapy with the first BTK inhibitor and/or; (iii) administering a treatment not comprising the first BTK inhibitor of step (a) or a second BTK inhibitor as monotherapy to such a subject that the subject is intolerant to the first BTK inhibitor; Or (c) (i) the cancer in the subject recurred during therapy with the first BTK inhibitor; (ii) the cancer in the subject is not responding to therapy with the first BTK inhibitor and/or; (iii) Also provided herein is a method of treating a subject having cancer comprising administering to such subject the subject is intolerant to the first BTK inhibitor an additional dose of the first BTK inhibitor. In some embodiments, the second BTK inhibitor is a compound of Formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof.

In some embodiments, the cancer is a BTK-associated cancer. In some embodiments, the BTK associated cancer exhibits at least one of point mutations/insertions/deletions and/or fusions as described in Tables 1, 1a and 4. In some embodiments, the BTK-associated cancer does not exhibit a BTK resistance mutation, e.g., any of the mutations described in Tables 2 and 3.

(a) detecting a dysregulation of the expression or activity or level of a BTK gene, a BTK kinase, or any of these; (b) administering one or more doses of a first BTK inhibitor to the subject having cancer for a predetermined period of time; (c) after (a) and (b), (i) the cancer in the subject relapsed during therapy with the first BTK inhibitor and/or; (ii) the cancer in the subject is not responding to therapy with the first BTK inhibitor and/or; (iii) determining whether the subject is intolerant to the first BTK inhibitor; And (d) (i) the cancer in the subject recurred during therapy with the first BTK inhibitor; (ii) the cancer in the subject is not responding to therapy with the first BTK inhibitor and/or; (iii) administering a treatment that does not include the BTK inhibitor of step (b) or a second BTK inhibitor as monotherapy to such a subject that the subject is intolerant to the first BTK inhibitor; Or (e) (i) the cancer in the subject recurred during therapy with the first BTK inhibitor; (ii) the cancer in the subject is not responding to therapy with the first BTK inhibitor and/or; (iii) Also provided herein is a method of treating a subject having cancer comprising administering to such subject the subject is intolerant to the first BTK inhibitor an additional dose of the first BTK inhibitor. In some embodiments, the second BTK inhibitor is a compound of Formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof.

In some embodiments, step (a) is performed before step (b).

In some embodiments, step (b) is performed before step (a).

In some embodiments, detecting a dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of these is followed by next-generation sequencing, immunohistochemistry, fluorescence microscopy, degraded FISH analysis, and PCR-based amplification ( For example, RT-PCR and quantitative real-time RT-PCR).

(a) detecting a dysregulation of the expression or activity or level of a BTK gene, a BTK kinase, or any of these; (b) administering one or more doses of a first BTK inhibitor to the subject having cancer for a predetermined period of time; (c) after (a) and (b), (i) the cancer in the subject relapsed during therapy with the first BTK inhibitor and/or; (ii) the cancer in the subject is not responding to therapy with the first BTK inhibitor and/or; (iii) determining whether the subject is intolerant to the first BTK inhibitor; And (d) (i) the cancer in the subject recurred during therapy with the first BTK inhibitor; (ii) the cancer in the subject is not responding to therapy with the first BTK inhibitor and/or; (iii) administering to such a subject that the subject is intolerant to the first BTK inhibitor, a treatment comprising at least one dose of a second BTK inhibitor; Or (e) (i) the cancer recurred during therapy with the first BTK inhibitor; (ii) the cancer in the subject is not responding to therapy with the first BTK inhibitor and/or; (iii) Also provided herein is a method of treating a subject having cancer comprising administering to such subject the subject is intolerant to the first BTK inhibitor an additional dose of the first BTK inhibitor. In some embodiments, the second BTK inhibitor is a compound of Formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof.

(a) detecting a dysregulation of the expression or activity or level of a BTK gene, a BTK kinase, or any of these; (b) administering one or more doses of a first BTK inhibitor to the subject having cancer for a predetermined period of time; (c) after (a) and (b), (i) the cancer in the subject relapsed during therapy with the first BTK inhibitor and/or; (ii) the cancer in the subject is not responding to therapy with the first BTK inhibitor and/or; (iii) determining whether the subject is intolerant to the first BTK inhibitor; And (d) (i) the cancer in the subject recurred during therapy with the first BTK inhibitor; (ii) the cancer in the subject is not responding to therapy with the first BTK inhibitor and/or; (iii) administering a treatment comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, amorphous or polymorphic form, a spray-dried dispersion thereof or a pharmaceutical composition thereof to such a subject in which the subject is intolerant to a first BTK inhibitor. The step of doing; Or (e) (i) the cancer in the subject recurred during therapy with the first BTK inhibitor; (ii) the cancer in the subject is not responding to therapy with the first BTK inhibitor and/or; (iii) Also provided herein is a method of treating a subject having cancer comprising administering to such subject the subject is intolerant to the first BTK inhibitor an additional dose of the first BTK inhibitor.

(a) detecting a dysregulation of the expression or activity or level of a BTK gene, a BTK kinase, or any of these; (b) administering one or more doses of a first BTK inhibitor to the subject having cancer for a predetermined period of time; (c) after (a) and (b), (i) the cancer in the subject relapsed during therapy with the first BTK inhibitor and/or; (ii) the cancer in the subject is not responding to therapy with the first BTK inhibitor and/or; (iii) determining whether the subject is intolerant to the first BTK inhibitor; And (d) (i) the cancer in the subject recurred during therapy with the first BTK inhibitor; (ii) the cancer in the subject is not responding to therapy with the first BTK inhibitor and/or; (iii) a compound of formula (I) or a pharmaceutically acceptable salt thereof, amorphous or polymorphic form, a spray-dried dispersion thereof or a pharmaceutical composition thereof and another anticancer agent or Administering a treatment comprising an anticancer therapy; Or (e) (i) the cancer in the subject recurred during therapy with the first BTK inhibitor; (ii) the cancer in the subject is not responding to therapy with the first BTK inhibitor and/or; (iii) Also provided herein is a method of treating a subject having cancer comprising administering to such subject the subject is intolerant to the first BTK inhibitor an additional dose of the first BTK inhibitor.

In some embodiments, step (a) is performed before step (b).

In some embodiments, step (b) is performed before step (a).

In some embodiments, detecting a dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of these is followed by next-generation sequencing, immunohistochemistry, fluorescence microscopy, degraded FISH analysis, and PCR-based amplification ( For example, RT-PCR and quantitative real-time RT-PCR).

(a) (i) the cancer in the subject having the cancer recurred during therapy with the first BTK inhibitor and/or; (ii) the cancer in the subject is not responding to therapy with the first BTK inhibitor and/or; (iii) determining whether the subject is intolerant to the first BTK inhibitor; And (b) (i) the cancer in the subject recurred during therapy with the first BTK inhibitor; (ii) the cancer in the subject is not responding to therapy with the first BTK inhibitor and/or; (iii) administering to such a subject that the subject is intolerant to the first BTK inhibitor, a treatment comprising at least one dose of a second BTK inhibitor; Or (c) (i) the cancer recurred during therapy with the first BTK inhibitor; (ii) the cancer in the subject is not responding to therapy with the first BTK inhibitor and/or; (iii) Also provided herein is a method of treating a subject having cancer comprising administering to such subject the subject is intolerant to the first BTK inhibitor an additional dose of the first BTK inhibitor. In some embodiments, the second BTK inhibitor is a compound of Formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof.

(a) (i) the cancer in the subject having the cancer recurred during therapy with the first BTK inhibitor and/or; (ii) the cancer in the subject is not responding to therapy with the first BTK inhibitor and/or; (iii) determining whether the subject is intolerant to the first BTK inhibitor; And (b) (i) the cancer in the subject recurred during therapy with the first BTK inhibitor; (ii) the cancer in the subject is not responding to therapy with the first BTK inhibitor and/or; (iii) treatment comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, amorphous or polymorphic form, a spray-dried dispersion thereof or a pharmaceutical composition thereof to such a subject that the subject is intolerant to a first BTK inhibitor. Administering; Or (c) (i) the cancer recurred during therapy with the first BTK inhibitor; (ii) the cancer in the subject is not responding to therapy with the first BTK inhibitor and/or; (iii) Also provided herein is a method of treating a subject having cancer comprising administering to such subject the subject is intolerant to the first BTK inhibitor an additional dose of the first BTK inhibitor.

(a) (i) the cancer in the subject having the cancer recurred during therapy with the first BTK inhibitor and/or; (ii) the cancer in the subject is not responding to therapy with the first BTK inhibitor and/or; (iii) determining whether the subject is intolerant to the first BTK inhibitor; And (b) (i) the cancer in the subject recurred during therapy with the first BTK inhibitor; (ii) the cancer in the subject is not responding to therapy with the first BTK inhibitor and/or; (iii) a compound of formula (I) or a pharmaceutically acceptable salt thereof, amorphous or polymorphic form, a spray-dried dispersion thereof or a pharmaceutical composition thereof and another anticancer agent or Administering a treatment comprising an anticancer therapy; Or (c) (i) the cancer recurred during therapy with the first BTK inhibitor; (ii) the cancer in the subject is not responding to therapy with the first BTK inhibitor and/or; (iii) Also provided herein is a method of treating a subject having cancer comprising administering to such subject the subject is intolerant to the first BTK inhibitor an additional dose of the first BTK inhibitor.

In some embodiments, the cancer is a BTK-associated cancer. In some embodiments, the BTK-associated cancer exhibits at least one of a point mutation/insertion/deletion as described in Tables 1, 1a or 4. In some embodiments, the BTK-associated cancer does not exhibit a BTK resistance mutation, e.g., any of the mutations described in Tables 2 and 3.

In some embodiments, the first BTK inhibitor is Ibrutinib, PRN1008, PRN473, ABBV-105, AC0058, Acalabrutinib, Janubrutinib, Sfebrutinib, Foceltinib, Evobrutinib, Tirablutinib, CG '806, ARQ 531, BIIB068, Becabrutinib, AS871, CB1763, CB988, GDC-0853, RN486, GNE-504, GNE-309, BTK Max, Dasatinib, CT-1530, CGI-1746, CGI-560 , LFM A13, TP-0158, dtrmwxhs-12, CNX-774 and LOU064. In some embodiments, the first BTK inhibitor is a covalent inhibitor, e.g., ibrutinib, PRN1008, PRN473, ABBV-105, AC0058, Acalabrutinib, Janubrutinib, Sfebrutinib, Poceltinib, Evobrutinib , M7583 or tirabrutinib. In some embodiments, the first BTK inhibitor is a non-covalent inhibitor, for example CG'806, ARQ 531, BIIB068, becabrutinib, AS871, CB1763, CB988, GDC-0853, RN486 or Dasatinib.

In some embodiments, the recurrence is an increase in the number of cancer cells in the subject after an improvement period, an increase in the size of one or more tumors in the subject, an increase in the tumor burden, an increase in the rate or degree of metastasis, a complete or partial symptom associated with cancer It is one or more of detection of exacerbation, increase in disease severity, and acceleration of disease progression. In some embodiments, the recurrence is progression of the cancer after a period of improvement. In some embodiments, the period of improvement is a decrease in the number of cancer cells in the subject, a decrease in the size of one or more tumors in the subject, a decrease in the tumor burden, a decrease in the rate or degree of metastasis, a total or partial improvement in symptoms associated with cancer, Reduction in the degree of disease, and slowing of disease progression.

In some embodiments, the cancer that does not respond to therapy with the first BTK inhibitor is an ongoing cancer. In some embodiments, the progression of the cancer is an increase in the number of cancer cells in the subject, an increase in the size of one or more tumors in the subject, an increase in tumor burden, an increase in the rate or degree of metastasis, a total or partial worsening of symptoms associated with the cancer. , Increasing the severity of the disease, and accelerating disease progression.

In some embodiments, a bone marrow biopsy, such as a bone marrow nuclear biopsy or a bone marrow aspirate specimen can be used to detect the progression or recurrence of a cancer, such as a blood cancer. In some embodiments, a bone marrow biopsy is performed by the percentage of blast cells, dysplasia (e.g., abnormal cells), percentage of lymphocytes, percentage of plasma cells, fibrosis, cellularity, distribution pattern of hematopoietic elements, morphology of lymphoid elements, and It can be used to detect one or more of the counts of lymphoid elements and plasma cells (eg, Sever, et al., Arch Pathol Lab Med. 2016 Sep;140(9):932-49) (which is The entirety of which is incorporated herein by reference). Bone marrow biopsy is a diagnostic process, a monitoring process, and a process of monitoring to determine one or more clinically significant parameters, including, but not limited to, disease progression and efficacy of therapy, recurrence of disease or occurrence of resistance mutations after administration of therapy to a subject / Or may be performed multiple times during the course of therapy. For example, during the course of diagnosis, monitoring and/or therapy, a first bone marrow biopsy may be performed at a first time point, and a second bone marrow biopsy may be performed at a second time point. In some embodiments, the first time point may be a time point before diagnosis of the subject as having a disease (e.g., when the subject is healthy), and the second time point may be a time point after the occurrence of the disease in the subject (e.g. For example, the second time point can be used to diagnose a subject having a disease). In some embodiments, the first time point can be a time point before diagnosing the subject as having the disease (e.g., when the subject is healthy), after which the subject is monitored, and the second time point is after monitoring the subject. It could be a point in time. In some embodiments, the first time point can be after the subject is diagnosed as having the disease, after which the therapy is administered to the subject, and the second time point can be after the therapy is administered; In this case, the second time point can be used to evaluate the efficacy of the therapy.

In some embodiments, the progression is one or more of an increase in the percentage of blast cells, an increase in the ratio of bone marrow to red blood cells, an increase in dysplasia (e.g., leukocyte dysplasia), an increase in the percentage of myeloid plasma cells, and an increase in the percentage of myeloid lymphocytes. It may include detecting. For example, progression is an increase in the percentage of blast cells at a second time point compared to the first time point, an increase in the ratio of bone marrow to red blood cells, an increase in dysplasia (e.g., leukocyte dysplasia), an increase in the percentage of myeloid plasma cells, and the bone marrow. Detecting one or more of the increase in the percentage of lymphocytes.

In some embodiments, the recurrence is of an increase in the percentage of blast cells, an increase in the ratio of bone marrow to red blood cells, an increase in dysplasia (e.g., leukocyte dysplasia), an increase in the percentage of myeloid plasma cells, and an increase in the percentage of myeloid lymphocytes after the improvement period. It may include detecting one or more. In some embodiments, the period of improvement is one of a decrease in the percentage of blast cells, a decrease in the ratio of bone marrow to red blood cells, a decrease in dysplasia (e.g., leukocyte dysplasia), a decrease in the percentage of myeloid plasma cells, and a decrease in the percentage of myeloid lymphocytes. It may include detecting an abnormality.

In some embodiments, the total blood count can be used to detect the progression or recurrence of a cancer, such as a hematologic cancer. In some embodiments, the whole blood cell count can be used to detect one or more of a percentage of white blood cells (eg, polymorphonuclear leukocytes) in peripheral blood, a decrease in platelet count, and a decrease in hemoglobin. The whole blood count is a diagnostic process, monitoring process to determine one or more clinically significant parameters, including, but not limited to, disease progression and efficacy of therapy, recurrence of disease, or occurrence of resistant mutations after administration of therapy to a subject. And/or multiple times during the course of therapy. For example, during the course of diagnosis, monitoring and/or therapy, a first whole blood cell count may be performed at a first time point, and a second whole blood cell count may be performed at a second time point. In some embodiments, the first time point may be a time point before diagnosis of the subject as having a disease (e.g., when the subject is healthy), and the second time point may be a time point after the occurrence of the disease in the subject (e.g. For example, the second time point can be used to diagnose a subject having a disease). In some embodiments, the first time point can be a time point before diagnosing the subject as having the disease (e.g., when the subject is healthy), after which the subject is monitored, and the second time point is after monitoring the subject. It could be a point in time. In some embodiments, the first time point can be after the subject is diagnosed as having the disease, after which the therapy is administered to the subject, and the second time point can be after the therapy is administered; In this case, the second time point can be used to evaluate the efficacy of the therapy.

In some embodiments, progression can include detecting one or more of an increase in the percentage of leukocytes (eg, polymorphonuclear leukocytes), a decrease in platelet count, and a decrease in hemoglobin in the peripheral blood. For example, progression involves detecting one or more of an increase in the percentage of white blood cells (e.g., polymorphonuclear leukocytes) in peripheral blood, a decrease in platelet count, and a decrease in hemoglobin at a second time point compared to the first time point. Can include.

In some embodiments, the recurrence may include detecting one or more of an increase in the percentage of white blood cells (e.g., polymorphonuclear leukocytes), a decrease in platelet count, and a decrease in hemoglobin in the peripheral blood after the improvement period. In some embodiments, the period of improvement may include detecting one or more of a decrease in the percentage of leukocytes (eg, polymorphonuclear leukocytes), an increase in platelet count, and an increase in hemoglobin in the peripheral blood.

In some embodiments, tumor burden can be assessed using PERCIST. In some embodiments, tumor burden is assessed using RECIST version 1.1.

In some embodiments, the cancer is lymphoma, and treatment of lymphoma is described in Cheson et al. J Clin Oncol. 2007, 25:579-86; Cheson et al., Blood. 2016, 128:2489-2496; And Cheson et al., Clin Oncol. 2014, 32(27):3059-3068] (each of which is incorporated herein by reference in its entirety).

In some embodiments, the cancer is leukemia, such as CLL, and treatment of leukemia is described in Hallek et al., Blood. 2008, 111(12):5446-56] (which is incorporated herein by reference in its entirety).

In some embodiments, the cancer is myeloma, and treatment of myeloma is described in Fujino et al., J Clin Exp Hematop. 2018, 58(2):61-67], which is evaluated by one or more of the methods described in the entirety of which is incorporated herein by reference.

In some embodiments, a liquid biopsy can be used to detect the progression of cancer. In some embodiments, a biological sample to be used for a liquid biopsy may include blood, plasma, urine, cerebrospinal fluid, saliva, sputum, broncho-alveolar lavage fluid, bile, lymph fluid, cyst, feces, ascites, and combinations thereof. In some embodiments, liquid biopsies can be used to detect circulating tumor cells (CTCs). In some embodiments, liquid biopsies can be used to detect cell-free DNA. In some embodiments, the cell-free DNA detected using a liquid biopsy is circulating tumor DNA (ctDNA) derived from tumor cells. Analysis of ctDNA (e.g., using sensitive detection techniques such as, but not limited to, next-generation sequencing (NGS), traditional PCR, digital PCR or microarray analysis) can be used to confirm the progression of cancer.

Liquid biopsy is a diagnostic process, monitoring process, and/or course of therapy to determine one or more clinically significant parameters, including, but not limited to, disease progression, efficacy of therapy, or development of resistance mutations after administration of therapy to a subject. Can be performed multiple times during. For example, during a diagnostic process, a monitoring process and/or a therapy process, a first liquid biopsy may be performed at a first time point, and a second liquid biopsy may be performed at a second time point. In some embodiments, the first time point may be a time point before diagnosis of the subject as having a disease (e.g., when the subject is healthy), and the second time point may be a time point after the occurrence of the disease in the subject (e.g. For example, the second time point can be used to diagnose a subject having a disease). In some embodiments, the first time point can be a time point before diagnosing the subject as having the disease (e.g., when the subject is healthy), after which the subject is monitored, and the second time point is after monitoring the subject. It could be a point in time. In some embodiments, the first time point can be after the subject is diagnosed as having the disease, after which the therapy is administered to the subject, and the second time point can be after the therapy is administered; In this case, the second time point can be used to evaluate the efficacy of the therapy (e.g., if the gene mutation(s) detected at the first time point is abundantly reduced or not detectable) or that has occurred as a result of therapy. It can be used to determine the presence of resistant mutations.

In some embodiments provided herein, the circulating tumor DNA is administered in a specific therapy (e.g., a first BTK inhibitor or a second BTK inhibitor, such as a compound of formula I or a pharmaceutically acceptable salt thereof, in an amorphous or polymorphic form, a spray thereof). -Dried dispersion or pharmaceutical composition thereof) to monitor the patient's responsiveness. For example, the therapy described herein (e.g., a first BTK inhibitor or a second BTK inhibitor, such as a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or Pharmaceutical compositions thereof), a biological sample can be obtained from a subject, and the level of circulating tumor DNA can be determined in the biological sample. This sample can be considered a baseline sample. The subject is then given one or more doses of a therapy as described herein (e.g., a first BTK inhibitor or a second BTK inhibitor, such as a compound of formula I or a pharmaceutically acceptable salt thereof, in an amorphous or polymorphic form, Spray-dried dispersions or pharmaceutical compositions thereof) can be administered and the level of circulating tumor DNA can be monitored (e.g., after a first dose, a second dose, a third dose, etc. or after 1 week, 2 After a week, 3 weeks, 4 weeks, etc.). When the level of circulating tumor DNA is lower than the baseline sample (e.g., 1% to about 99% decrease, 1% to about 95% decrease, 1% to about 90% decrease, 1% to about 85% decrease, 1% to about 80% reduction, 1% to about 75% reduction, 1% reduction to about 70% reduction, 1% reduction to about 65% reduction, 1% reduction to about 60% reduction, 1% reduction to about 55% Decrease, 1% decrease to about 50% decrease, 1% decrease to about 45% decrease, 1% decrease to about 40% decrease, 1% decrease to about 35% decrease, 1% decrease to about 30% decrease, 1% decrease To about 25% decrease, 1% to about 20% decrease, 1% to about 15% decrease, 1% to about 10% decrease, 1% to about 5% decrease, about 5% to about 99% decrease, About 10% to about 99% reduction, about 15% to about 99% reduction, about 20% to about 99% reduction, about 25% to about 99% reduction, about 30% to about 99% reduction, about 35% to about 99% decrease, about 40% to about 99% decrease, about 45% to about 99% decrease, about 50% to about 99% decrease, about 55% to about 99% decrease, about 60% to about 99% decrease, about 65% to about 99% reduction, about 70% to about 99% reduction, about 75% to about 95% reduction, about 80% to about 99% reduction, about 90% reduction to about 99% reduction, about 95% to about 99% decrease, about 5% to about 10% decrease, about 5% to about 25% decrease, about 10% to about 30% decrease, about 20% to about 40% decrease, about 25% to about 50% decrease, about 35% to about 55% reduction, about 40% to about 60% reduction, about 50% reduction to about 75% reduction, about 60% reduction to about 80% reduction, or about 65% to about 85% reduction, etc.), which Shows responsiveness to therapy. In some embodiments, the level of circulating tumor DNA in a biological sample (n) obtained from a patient is compared to a sample (n-1) taken immediately previously. When the level of circulating tumor DNA in the n sample is lower than the n-1 sample (e.g., 1% to about 99% decrease, 1% to about 95% decrease, 1% to about 90% decrease, 1% to About 85% reduction, 1% to about 80% reduction, 1% to about 75% reduction, 1% reduction to about 70% reduction, 1% reduction to about 65% reduction, 1% reduction to about 60% reduction, 1% Decrease to about 55%, 1% to about 50%, 1% to about 45%, 1% to about 40%, 1% to about 35%, 1% to about 30% Decrease, 1% decrease to about 25% decrease, 1% decrease to about 20% decrease, 1% decrease to about 15% decrease, 1% decrease to about 10% decrease, 1% to about 5% decrease, about 5% to About 99% reduction, about 10% to about 99% reduction, about 15% to about 99% reduction, about 20% to about 99% reduction, about 25% to about 99% reduction, about 30% to about 99% reduction, About 35% to about 99% reduction, about 40% to about 99% reduction, about 45% to about 99% reduction, about 50% to about 99% reduction, about 55% to about 99% reduction, about 60% to about 99% decrease, about 65% to about 99% decrease, about 70% to about 99% decrease, about 75% to about 95% decrease, about 80% to about 99% decrease, about 90% decrease to about 99% decrease, About 95% to about 99% reduction, about 5% to about 10% reduction, about 5% to about 25% reduction, about 10% to about 30% reduction, about 20% to about 40% reduction, about 25% to about 50% reduction, about 35% to about 55% reduction, about 40% to about 60% reduction, about 50% reduction to about 75% reduction, about 60% reduction to about 80% reduction, or about 65% to about 85% Reduction, etc.), which indicates a responsiveness to therapy. If responsive to therapy, the subject may be administered one or more doses of therapy, and circulating tumor DNA may continue to be monitored.

When the level of circulating tumor DNA in the sample is higher than baseline (e.g., 1% to about 99% increase, 1% to about 95% increase, 1% to about 90% increase, 1% to about 85% increase , 1% to about 80% increase, 1% to about 75% increase, 1% increase to about 70% increase, 1% increase to about 65% increase, 1% increase to about 60% increase, 1% increase to about 55 % Increase, 1% increase to about 50% increase, 1% increase to about 45% increase, 1% increase to about 40% increase, 1% increase to about 35% increase, 1% increase to about 30% increase, 1% Increase to about 25% increase, 1% increase to about 20% increase, 1% increase to about 15% increase, 1% increase to about 10% increase, 1% to about 5% increase, about 5% to about 99% increase , From about 10% to about 99% increase, from about 15% to about 99% increase, from about 20% to about 99% increase, from about 25% to about 99% increase, from about 30% to about 99% increase, from about 35% to About 99% increase, about 40% to about 99% increase, about 45% to about 99% increase, about 50% to about 99% increase, about 55% to about 99% increase, about 60% to about 99% increase, About 65% to about 99% increase, about 70% to about 99% increase, about 75% to about 95% increase, about 80% to about 99% increase, about 90% increase to about 99% increase, about 95% to About 99% increase, about 5% to about 10% increase, about 5% to about 25% increase, about 10% to about 30% increase, about 20% to about 40% increase, about 25% to about 50% increase, About 35% to about 55% increase, about 40% to about 60% increase, about 50% increase to about 75% increase, about 60% increase to about 80% increase, or about 65% to about 85% increase, etc.), This can indicate the progression of cancer. When the level of circulating tumor DNA in the n sample is higher than the n-1 sample (e.g., 1% to about 99% increase, 1% to about 95% increase, 1% to about 90% increase, 1% to About 85% increase, 1% to about 80% increase, 1% to about 75% increase, 1% increase to about 70% increase, 1% increase to about 65% increase, 1% increase to about 60% increase, 1% Increase to about 55% increase, 1% increase to about 50% increase, 1% increase to about 45% increase, 1% increase to about 40% increase, 1% increase to about 35% increase, 1% increase to about 30% Increase, 1% increase to about 25% increase, 1% increase to about 20% increase, 1% increase to about 15% increase, 1% increase to about 10% increase, 1% to about 5% increase, about 5% increase About 99% increase, about 10% to about 99% increase, about 15% to about 99% increase, about 20% to about 99% increase, about 25% to about 99% increase, about 30% to about 99% increase, About 35% to about 99% increase, about 40% to about 99% increase, about 45% to about 99% increase, about 50% to about 99% increase, about 55% to about 99% increase, about 60% to about 99% increase, about 65% to about 99% increase, about 70% to about 99% increase, about 75% to about 95% increase, about 80% to about 99% increase, about 90% increase to about 99% increase, About 95% to about 99% increase, about 5% to about 10% increase, about 5% to about 25% increase, about 10% to about 30% increase, about 20% to about 40% increase, about 25% to about 50% increase, about 35% to about 55% increase, about 40% to about 60% increase, about 50% increase to about 75% increase, about 60% increase to about 80% increase, or about 65% to about 85% Increase, etc.), which may indicate the progression of cancer. If progression of cancer is suspected during therapy with the first BTK inhibitor, the subject may undergo one or more of imaging, biopsy, surgery, or other diagnostic tests. In some embodiments, if progression of cancer is suspected during therapy with a first BTK inhibitor, the subject is a second BTK inhibitor, e.g., a compound of Formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof Spray-dried dispersions thereof or pharmaceutical compositions thereof can be administered (either alone or in combination with previous therapies).

After a period of improvement, e.g., a period of responsiveness to therapy as described above, if the level of circulating tumor DNA in the sample is higher than the level obtained during the period of improvement (e.g., 1% to about 99% increase, 1% to about 95% increase, 1% to about 90% increase, 1% to about 85% increase, 1% to about 80% increase, 1% to about 75% increase, 1% increase to about 70% increase, 1 % Increase to about 65% increase, 1% increase to about 60% increase, 1% increase to about 55% increase, 1% increase to about 50% increase, 1% increase to about 45% increase, 1% increase to about 40 % Increase, 1% increase to about 35% increase, 1% increase to about 30% increase, 1% increase to about 25% increase, 1% increase to about 20% increase, 1% increase to about 15% increase, 1% Increase to about 10% increase, 1% to about 5% increase, about 5% to about 99% increase, about 10% to about 99% increase, about 15% to about 99% increase, about 20% to about 99% increase , About 25% to about 99% increase, about 30% to about 99% increase, about 35% to about 99% increase, about 40% to about 99% increase, about 45% to about 99% increase, about 50% to About 99% increase, about 55% to about 99% increase, about 60% to about 99% increase, about 65% to about 99% increase, about 70% to about 99% increase, about 75% to about 95% increase, About 80% to about 99% increase, about 90% increase to about 99% increase, about 95% to about 99% increase, about 5% to about 10% increase, about 5% to about 25% increase, about 10% to About 30% increase, about 20% to about 40% increase, about 25% to about 50% increase, about 35% to about 55% increase, about 40% to about 60% increase, about 50% increase to about 75% increase , An increase of about 60% to about 80%, or an increase of about 65% to about 85%, etc. ), which may indicate a recurrence of cancer. When the level of circulating tumor DNA in the n sample is higher than the n-1 sample (e.g., 1% to about 99% increase, 1% to about 95% increase, 1% to about 90% increase, 1% to About 85% increase, 1% to about 80% increase, 1% to about 75% increase, 1% increase to about 70% increase, 1% increase to about 65% increase, 1% increase to about 60% increase, 1% Increase to about 55% increase, 1% increase to about 50% increase, 1% increase to about 45% increase, 1% increase to about 40% increase, 1% increase to about 35% increase, 1% increase to about 30% Increase, 1% increase to about 25% increase, 1% increase to about 20% increase, 1% increase to about 15% increase, 1% increase to about 10% increase, 1% to about 5% increase, about 5% increase About 99% increase, about 10% to about 99% increase, about 15% to about 99% increase, about 20% to about 99% increase, about 25% to about 99% increase, about 30% to about 99% increase, About 35% to about 99% increase, about 40% to about 99% increase, about 45% to about 99% increase, about 50% to about 99% increase, about 55% to about 99% increase, about 60% to about 99% increase, about 65% to about 99% increase, about 70% to about 99% increase, about 75% to about 95% increase, about 80% to about 99% increase, about 90% increase to about 99% increase, About 95% to about 99% increase, about 5% to about 10% increase, about 5% to about 25% increase, about 10% to about 30% increase, about 20% to about 40% increase, about 25% to about 50% increase, about 35% to about 55% increase, about 40% to about 60% increase, about 50% increase to about 75% increase, about 60% increase to about 80% increase, or about 65% to about 85% Increase, etc.), which may indicate a recurrence of cancer. If a recurrence of the cancer is suspected during therapy with the first BTK inhibitor, the subject may undergo one or more of imaging, biopsy, surgery, or other diagnostic tests. In some embodiments, if a recurrence of the cancer is suspected during therapy with a first BTK inhibitor, the subject is a second BTK inhibitor, e. Spray-dried dispersions thereof or pharmaceutical compositions thereof can be administered (either alone or in combination with previous therapies). See, eg, Cancer Discov; 7(12); 1368-70 (2017); And Cancer Discov; 7(12); 1394-403 (2017). In some embodiments, no BTK resistance mutations, e.g., none of the mutations described in Tables 2 and 3, are detected.

In some embodiments, the subject intolerant to the first BTK inhibitor is a severe, disability or life-threatening adverse event during therapy with the first BTK inhibitor, unplanned hospitalization during therapy with the first BTK inhibitor, first BTK Had one or more of discontinuation of therapy with the inhibitor, a decrease in the dose of the first BTK inhibitor, a functional decrease due to therapy with the first BTK inhibitor, and a decrease in performance status.

In some embodiments, performance status is assessed using the Eastern Collaborative Oncology Group (ECOG) Performance Status Scale.

In some embodiments, performance status is assessed using Karnowski performance status.

In some embodiments, performance status is assessed by a Lansky performance score.

In some embodiments, (i) the subject's cancer has recurred during therapy with the first BTK inhibitor; (ii) the subject's cancer is not responding to therapy with the first BTK inhibitor; (iii) When the subject is intolerant to the first BTK inhibitor, none of the BTK resistance mutations, e.g., the mutations listed in Tables 2 and 3, are detected.

In some embodiments, (i) the subject's cancer has recurred during therapy with the first BTK inhibitor; (ii) the subject's cancer is not responding to therapy with the first BTK inhibitor; (iii) When the subject is intolerant to the first BTK inhibitor, none of the BTK resistance mutations, e.g., the mutations listed in Tables 2 and 3, are detected.

Some examples of these methods include the subject's clinical record (e.g., a computer readable medium) that the subject should be administered a treatment that does not include the first BTK inhibitor in step (a) or a different BTK inhibitor as a future monotherapy. It further includes the step of recording in.

In some of any of the above embodiments, the subject does not have active uncontrolled autoimmune cytopenia. In some embodiments, the subject has not been diagnosed with autoimmune cytopenia. In some embodiments, the subject does not have a history of clinically significant uncontrolled heart, cardiovascular disease, or myocardial infarction within 6 months of initiating treatment as described herein. In some embodiments, the subject has not been diagnosed with a heart or cardiovascular disease. In some embodiments, the subject did not have a myocardial infarction. In some embodiments, the subject does not have a clinically significant active malabsorption syndrome. In some embodiments, the subject has not been diagnosed with malabsorption syndrome. In some embodiments, the subject has a strong cytochrome P450 3A4 (CYP3A4) inhibitor (e.g., ritonavir, indinavir, nelpinavir, saquinavir, clarithromycin, telithromycin) during any treatment as described herein. Tromycin, chloramphenicol, ketoconazole, itraconazole, posaconazole, voriconazole, nefazodone and cobicistat) or an inducer (e.g. carbamazepine, dexamethasone, etosuccimide, glucocorticoid, griseofulvin, phenytoin) , Primidone, progesterone, rifampin, naphcillin, nlpinavir, nevirapine, oxcarbazepine, phenobarbital, phenylbutazone, rofecoxib (mild), St. John's wort, sulfadimidine, sulfinpyrazone and troglitazone) It is not being treated with. In some embodiments, the subject is treated with a proton pump inhibitor (e.g., omeprazole, lansoprazole, dexlansoprazole, esomeprazole, pantoprazole, rabeprazole, ilaprazole) within 7 days of initiating any treatment described herein. Not being cured. In some embodiments, the subject does not have an active second malignancy. In some embodiments, the subject has an active second malignancy in remission and the subject has an life expectancy of> 2 years.

Idiopathic pulmonary fibrosis or autoimmune or inflammatory diseases such as arthritis (e.g. rheumatoid arthritis), multiple sclerosis, osteoporosis, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, chronic urticaria, myasthenia gravis and lupus (e.g. , Lupus erythematosus) to a subject diagnosed with (or confirmed to have) a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical composition thereof Also provided herein is a method of treating the subject comprising administering.

Subjects identified or diagnosed as having BTK-associated idiopathic pulmonary fibrosis or autoimmune or inflammatory disease (e.g., in a biopsy sample from a subject or subject A therapeutically effective amount of a formula in subjects identified or diagnosed with BTK-associated idiopathic pulmonary fibrosis or an autoimmune or inflammatory disease) through the use of regulatory agency-approved, e.g., FDA-approved kits to identify dysregulation Also provided herein is a method of treating a subject comprising administering a compound of I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof.

(a) determining whether idiopathic pulmonary fibrosis or autoimmune or inflammatory disease is BTK-associated idiopathic pulmonary fibrosis or autoimmune or inflammatory disease in a subject in need of treatment for idiopathic pulmonary fibrosis or autoimmune or inflammatory disease (e.g. For example, using a regulatory-authorized, e.g., FDA-approved kit for identifying dysregulation of the expression or activity or level of a BTK gene, BTK kinase, or any of these in a subject or a biopsy sample from a subject. Or by performing any of the non-limiting examples of the assays described herein); And (b) when idiopathic pulmonary fibrosis or autoimmune or inflammatory disease is determined to be BTK-associated IBS, to the subject a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray thereof. Also provided is a method of treating idiopathic pulmonary fibrosis or an autoimmune or inflammatory disease in said subject comprising administering a dried dispersion or a pharmaceutical composition thereof.

In some embodiments, the compounds of the invention are idiopathic pulmonary fibrosis or autoimmune in combination with one or more additional therapeutic agents or therapies effective in treating idiopathic pulmonary fibrosis or autoimmune or inflammatory disease, acting by the same or different mechanisms of action. Or it is useful for treating inflammatory diseases. At least one additional therapeutic agent is a compound of formula (I) or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical composition thereof, together with the same or as part of a separate dosage form, the same Or via different routes of administration, and with the same or different dosing schedules according to standard pharmaceutical practice known to those skilled in the art.

Thus, (a) a compound of formula I or a pharmaceutical thereof for simultaneous, separate or sequential use for the treatment of idiopathic pulmonary fibrosis or autoimmune or inflammatory disease in a subject in need thereof Idiopathic pulmonary fibrosis, comprising a phase acceptable salt, amorphous or polymorphic form, a spray-dried dispersion thereof or a pharmaceutical composition thereof, (b) an additional therapeutic agent and (c) optionally at least one pharmaceutically acceptable carrier. Or administering a pharmaceutical combination for the treatment of an autoimmune or inflammatory disease, wherein a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical thereof Also provided herein is a method of treating idiopathic pulmonary fibrosis or an autoimmune or inflammatory disease, wherein the amount of the composition and the additional therapeutic agent together are effective to treat idiopathic pulmonary fibrosis or an autoimmune or inflammatory disease. In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical composition thereof and an additional therapeutic agent are administered simultaneously as separate dosages. In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical composition thereof and the additional therapeutic agent are sequentially, in any order, as individual dosages, It is administered in a combined therapeutically effective amount, for example daily or in intermittent dosages. In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical composition thereof and an additional therapeutic agent are administered simultaneously as a combined dosage.

(i) for simultaneous, separate or sequential use for the treatment of idiopathic pulmonary fibrosis or autoimmune or inflammatory diseases (a) a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, spray-dried thereof Dispersion or pharmaceutical composition thereof, (b) at least one additional therapeutic agent (e.g., any exemplary addition described herein or known in the art for treating idiopathic pulmonary fibrosis or autoimmune or inflammatory diseases Of the therapeutic agent) and (c) optionally at least one pharmaceutically acceptable carrier, wherein a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical thereof The amount of the composition and the additional therapeutic agent together is effective in treating idiopathic pulmonary fibrosis or autoimmune or inflammatory disease, idiopathic pulmonary fibrosis or autoimmune or inflammatory disease in a subject in need of treatment of idiopathic pulmonary fibrosis or autoimmune or inflammatory disease A pharmaceutical combination for treating a disease; (ii) pharmaceutical compositions comprising such combinations; (iii) the use of such a combination for the manufacture of a medicament for the treatment of rheumatoid arthritis or irritable bowel syndrome; And (iv) a commercial package or product comprising such a combination as a combination formulation for simultaneous, separate or sequential use; And methods of treating idiopathic pulmonary fibrosis or autoimmune or inflammatory disease in a subject in need thereof. In one embodiment, the subject is a human.

In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof or a pharmaceutical composition thereof and the additional therapeutic agent are formulated as separate unit dosage forms, wherein individual administration The form is suitable for sequential or simultaneous administration. They also apply to cocktail therapy, for example the administration of three or more active ingredients.

Also provided is a method of inhibiting BTK kinase activity in a cell comprising the step of contacting the cell with a compound of formula (I). In one embodiment, the contact is an in vitro contact. In one embodiment, the contact is an in vivo contact. In one embodiment, the contacting is in vivo contact, wherein the method is an effective amount of a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, spray-dried thereof to a subject having cells having BTK kinase activity. And administering the dispersion or pharmaceutical composition thereof. In some embodiments, the cell is a cancer cell. In one embodiment, the cancer cell is any cancer as described herein. In some embodiments, the cancer cell is a BTK-associated cancer cell. In some embodiments, the cell is a B-cell.

Also provided is a method of inhibiting BTK kinase activity in a mammalian cell comprising the step of contacting the cell with a compound of formula (I). In one embodiment, the contact is an in vitro contact. In one embodiment, the contact is an in vivo contact. In one embodiment, the contacting is in vivo contact, wherein the method is an effective amount of a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, spray-dried thereof to a mammal having cells having BTK kinase activity. And administering the prepared dispersion or pharmaceutical composition thereof. In some embodiments, the mammalian cell is a mammalian cancer cell. In one embodiment, the mammalian cancer cell is any cancer as described herein. In some embodiments, the mammalian cancer cell is a BTK-associated cancer cell. In some embodiments, the mammalian cell is a B-cell.

In vitro or comprising the step of contacting the cell with an effective amount of a compound of formula I as defined herein, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. Methods of inhibiting cell proliferation in vivo are also provided herein.

4. Kit

Pharmaceuticals useful for the treatment of, for example, BTK-associated diseases or disorders, such as cancer or idiopathic pulmonary fibrosis or autoimmune or inflammatory disorders, comprising one or more containers containing a therapeutically effective amount of a pharmaceutical composition comprising a compound provided herein. Kits are provided herein. Such kits will be apparent to those skilled in the art, and if desired, a container having one or more of the components of a variety of conventional pharmaceutical kits, such as, for example, one or more pharmaceutically acceptable carriers, additionally It may further include a container of. Instructions as inserts or labels indicating the amount of ingredients to be administered, guidelines for administration and/or guidelines for mixing ingredients may also be included in the kit.

Example

The following examples illustrate the invention.

Example 1: BTK activity assay

A. BTK activity assay for mutants of BTK

The activity of the compounds of formula I against full-length wild-type (WT) and mutant human BTK enzymes into the poly-glutamic acid-tyrosine (poly-EY) peptide substrate ^{of [33} P]-PO ₄ ^{from [γ- 33} P]-ATP It was determined by monitoring the incorporation of. The reaction mixture each contained polyhistidine-tagged BTK enzyme, poly-EY and BTK inhibitor in appropriate concentrations. After incubation for 20 min the reaction mixture at room temperature, [[γ- ³³ P] -ATP was added to (radiochemical concentration of 10 μCi / μL) to a 10 μM concentration or ATP concentration K _m for the respective enzyme. After incubation for 2 hours at room temperature, the radiolabeled peptide substrate was captured, and the incorporated radioactivity was quantified. Compounds of Formula I were tested for ibrutinib and acalabrutinib resistance mutations, BTK WT, BTK C481S, preclinically active BTK mutants, BTK E41K, and clinically observed lung cancer mutations, BTK P190K. I did. At 10 μM ATP, the IC50 values for compounds of formula I were 0.95 nM and 0.29 nM for BTK and BTK C481S, respectively. At the K _m ATP concentration, the compounds of formula I inhibited BTK WT, BTK C481S, BTK E41K and BTK P190K with IC50 values of 3.15, 1.42, 7.85 and 2.14 nM, respectively.

B. Kinase Selectivity Assay

Compounds of Formula I were tested for inhibition of 371 kinases using a radiolabeled ATP activity assay (Reactive Biology Wild Type Kinase Profiler). Each assay was performed at an ATP concentration close to the K _{m for each enzyme.} At a compound concentration of Formula I of 1.0 μM, _{approximately 320 times greater than IC 50} for human wild-type BTK enzyme and _{approximately 700 times greater than IC 50} for BTK C481S mutant enzyme, only 8 of 371 kinases other than BTK : BRK, CSK, ERBB4, FYN, MEK1, MEK2, TXK and YES1 showed percent control (POC) values less than 50 (equivalent to greater than 50% inhibition). The inhibitory activity of compounds of formula I on the enzymatic activity of these kinases and TECs was determined using a radiolabeled ATP activity assay performed with ATP concentrations near the ATP _{K m for each enzyme.} After co-incubation with serial dilutions of the compound of formula I, ^{the amount of 33} P incorporated into the peptide substrate was determined and the data analyzed using standard curve fitting methods. The results are presented in Table 5.

Table 5. Comparison of _{IC 50 values}

Example 2: Polymorph Screen for Compounds of Formula I

A. Instruments and methods of analysis

The analysis instruments and methods used in the polymorph screens described in this example are as follows.

X-ray powder diffraction (XRPD)

XRPD analysis was performed on a Bruker D5000 diffractometer in Bragg-Brentano configuration. Approximately 1 mg of each sample was mounted on a silicon base for analysis. The data was smoothed using a Fourier algorithm and the background was subtracted from each diffractogram. The following experimental parameters were used.

● Source: CuKα

● Wavelength: 1.5406 Å

● Scan range: 2-40° (2θ)

● Step size: 0.01° (2θ)

● Time per step: 4.0 seconds

● Source voltage: 40 kV

● Source current: 30 mA

● Divergence slit width: 2 mm

● Anti-scattering slit width: 2 mm

● Detector slit width: 0.2 mm

● Sample rotation: none

Nuclear magnetic resonance (NMR) spectroscopy

NMR experiments were performed on a Bruker DRX500 spectrometer, equipped with a 5 mm ¹ H-wideband normal geometry probehead and operating at 500.13 MHz for protons.

Differential Scanning Calorimetry (DSC)

Samples were packed into an aluminum DSC equipped with a perforated lid. The sample pan was then loaded into a METTLER TOLEDO 823 calorimeter connected to a TA8000 workstation.

B. Initial characterization

Many crystallization conditions for the compound of formula I were screened, and the observed solids were analyzed by XRPD to determine the morphology and degree of crystallinity. The results are presented in Table 6 below.

Table 6. Polymorphic screening

C. Polymorph Form A of Compounds of Formula I

For sample 67, approximately 10 mg of the compound of formula I was weighed into a glass vial and dissolved in methanol to give a saturated solvent. Then the solvent was evaporated at 25° C. while stirring. After the compound of formula I precipitated from the solution, crystals were collected through filtration. The compound of formula I was analyzed by XRPD (Figure 1) and identified as Form A.

D. Polymorph Form B of Compounds of Formula I

For sample 7, approximately 10 mg of the compound of formula I was weighed into a glass vial and dissolved in methanol to give a saturated solvent. Then the solvent was evaporated at 25° C. with stirring, and crystals were collected. Form B crystallized as a mixture with Form A in methanol. The DSC of the mixture of Forms A and B showed little exotherm with an onset temperature of approximately 120° C. and an onset temperature of the melt (possibly a melt of Form B) at approximately 145° C. (FIG. 2A ). Following the melt at approximately 145° C., an exothermic event occurred due to the conversion of the melt to Form A. The endothermic event with an onset temperature of 180° C. was attributed to the melt of Form A. A pure sample of Form B was required to determine the DSC curve for Form B. ^{2B shows the 1} H spectrum of a mixture of Form A and Form B.

E. Polymorph Form C of Compounds of Formula I

For sample 32, approximately 10 mg of the compound of formula I was weighed into a glass vial and dissolved in 1,4-dioxane to give a saturated solvent. Then the solvent was evaporated at 25° C. with stirring, and crystals were collected. ^{Based on the 1} H NMR spectrum, Form C was a hemi-1,4-dioxane solvate (Fig. 3A). The DSC curve of Form C showed an endotherm at 40-110° C. associated with the loss of 1,4-dioxane (FIG. 3B ). An endothermic event followed by a small exothermic event followed by a melt endotherm due to the melting of Form A. Desolvation can take place to give a homogeneous desolvate or a different physical form before it can be converted to polymorph Form A.

F. Other Methods of Preparing Form A of Compound I

About 10 g of the compound of formula I was suspended in isopropanol (50 mL, 5 mL/g) and dissolved by heating. The warm solution was polish filtered and allowed to cool slowly to room temperature. The resulting solid was collected by filtration and dried to give 8.57 g (86%) of a compound of formula I as Form A by XRPD.

About 20 g of the compound of formula I was suspended in isopropanol (50 mL, 5 mL/g) and dissolved by heating. The warm solution was polish filtered and added to the reactor containing water (70 mL, 7 vol). The resulting solid was collected by filtration and dried to give 18.47 g (92%) of a compound of formula I as Form A by XRPD.

About 15.1 g of the compound of formula I was suspended in ethanol (76 mL, 5 mL/g) and dissolved by heating (about 70° C.). The warm solution was polish filtered into a jacketed container and allowed to cool to ˜59° C., to which a compound Form A seed (15 mg) of Formula I was charged. The reactor was cooled to 55° C. and heptane (91 mL, 6 mL/g) was added dropwise over 4 hours. The suspension was cooled to 15° C. over 1 hour. The resulting solid was collected by filtration, washed with ethanol:heptane (5:6 ratio, 30 mL, 2 mL/g) and dried to give 10.3 g (68%) of a compound of formula I as Form A by XRPD. Obtained.

About 2.5 g of the compound of formula I was suspended in ethyl acetate (25 mL, 10 mL/g) and dissolved by heating (~75[deg.] C.). Then it was allowed to cool to -45°C, and after seeding with compound form A of formula I, heptane (22.5 mL, 9 mL/g) was slowly added. The suspension was held at 45° C. overnight and then allowed to cool to 24° C. The resulting solid was collected by filtration and dried to give 1.6 g (64%) of a compound of formula I as Form A by XRPD.

Example 3: Large-scale preparation of Form A of compound of formula I

A. Experimental procedure

In a 1 L cylindrical reactor the compound of formula I [non-form A intermediate grade (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1 -(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide] (80.0 g, 167 mmol, 1.0 eq) was charged. Methanol (600 mL, 7.5 vol) was added and the suspension was stirred at room temperature until all solids were dissolved. The solution was polish filtered and the filtrate was transferred to a clean dry 5 L cylindrical jacketed reactor. Methanol (40 mL, 0.5 vol) was used to aid in the transfer of organics to the reactor. The solution was heated to 55±5°C. Water (640 mL, 8 vol) was charged through the addition funnel over the course of 2 hours at a rate of -5.33 mL/min. A suspension was formed. The reactor was cooled to 15±5° C. at a rate of 10° C./hour and stirred at room temperature overnight. The solid was filtered over polypropylene cloth (in a Buchner funnel), washed with 1:1 water:methanol (2 x 80 mL, 2 x 1 vol), removed and dried on the filter cake for -10 minutes. The solid was dried in a vacuum oven at 55° C. until a constant mass was achieved, yielding 74.0 g of a tan crystalline/sandy solid of the compound of formula I showing 100 area% HPLC purity.

B. Form A of compounds of formula I

The compound of formula I, prepared as described in Example 3A, ^{was analyzed by XRPD, 1} H NMR and DSC/TGA and identified as Form A. The X-ray powder diffraction scan of Form A is shown in Figure 4A. The X-ray powder diffraction peaks of Form A are shown in Table 7. ^{The 1} H NMR spectrum is presented in Figure 4b. An endothermic event was observed at an onset temperature of approximately 185° C. by DCS (FIG. 4C ).

Table 7. XRPD peaks of Form A of compound of formula I

Example 4: Preparation of spray-dried dispersion of compound of formula I (SDI/SDD)

A. Solubility screening

The solubility of the compound of formula I was tested at different pH values in aqueous solution as shown in Table 8.

Table 8. Water solubility of compounds of formula I at different pH values

The solubility of the compound of formula I was 14-17 μg/mL at pH 1 to pH 10.

The solubility of the compound of formula I was also tested under conditions simulating intestinal fluid (fasting artificial intestinal fluid [FaSSIF], fed artificial intestinal fluid [FeSSIF] and fasting artificial gastric fluid [FaSSGF]) as shown in Table 9.

Table 9. Kinetic solubility of compounds of formula I in FaSSGF, FaSSIF and FeSSIF media

The solubility of the compound of formula I in the lipid vehicle was also investigated. Compound Form A of formula (I) is added into a clear 20 mL glass vial, followed by corresponding excipients such as MIGLYOL® 812 (saturated coconut and palm kernel oil-derived caprylic and capric fatty acids and glycerin. , For example C8 and C10 triglycerides), CAPMUL® MCM EP (glyceryl monocaprylocaprate type I (EP)), PECEOL ^™ (glycerol monooleate (type 40) EP, Glyceryl Monooleate (Type 40) NF), LABRAFIL® M2125CS (Linoleoyl Polyoxyl-6 Glyceride), LAUROGLYCOL ^TM FCC (Propylene Glycol Monolaurate (Type I)) , Span® 80 (sorbitan monooleate), PHOSAL® 53 MCT (lecithin in caprylic/capric triglycerides, alcohol, glyceryl stearate, oleic acid and ascorbyl palmitate), Or Capmul PG-8 (propylene glycol monocaprylate) was added. The sample was then homogenized with a handheld homogenizer for 10 minutes until the compound of formula I was visibly dissolved. Samples were mixed overnight at ambient conditions. A set of matched control formulations was also prepared. Excipient screens for lipid-based formulations show that the solubility of the compound of formula I is PEG 400, LABRASOL® ALF (e.g. caprylocaproyl polyoxyl-8 glyceride), KOLLIPHOR® EL (E.g., polyoxyl castor oil), Tween 80 and vitamin E TPGS showed the best.

Table 10. Summary of Solubility Screening in Lipid Vehicles

API refers to the active pharmaceutical ingredient.

Of the excipients tested, the compound of formula I is the most soluble among Labrasol® ALF and PEG-400.

B. Spray-drying solid dispersions of compounds of formula I

Solubility screening in organic solvents showed that methanol, acetone, dichloromethane, 95:5 tetrahydrofuran:water and 80:20 dichloromethane:methanol are suitable solvents for spray-drying. Compounds of formula I and HPMCAS-MG (granulated hypromellose acetate having an acetyl content of about 7% to about 11% and a succinoyl content of about 10% to about 14%), HPMC E3 (29% methoxyl groups And hypromellose with an average content of 10% hydroxypropyl groups), Kollidon® VA64 (vinylpyrrolidone-vinyl acetate copolymer with an average particle size of about 50 μm to about 250 50 μm) or PVPK30 (44,000 Four spray-dried dispersions (SDDs) were prepared comprising a polyvinylpyrrolidone polymer having an average molecular weight of 54,000 g/mol). The composition of the developed formulation is shown in Tables 11 and 12.

Table 11. Candidate spray-dried dispersion formulations of compounds of formula I

Table 12. Candidate spray solution composition

The prepared spray-dried dispersion prototypes were evaluated by mDSC (Figure 5), XRPD (Figure 6) and TGA (Figure 7). The main results are summarized in Table 13.

Table 13. Analysis after drying

Both the XRPD and mDSC data confirmed that the four prototypes were amorphous and there were no detectable levels of crystalline material. All 4 types of SDI were stable for 2 weeks at 40°C with regard to purity and amorphous form.

C. Spray solution and spray

A spray solution was prepared by adding dichloromethane (14.3 kg) and methanol (3.6 kg) to a 36 L stainless steel mixing vessel. HPMCAS-MG (984 g) was added to the solvent system while mixing with a top down mixer in a medium vortex until the polymer was completely solubilized. The compound of formula I (995 g, corrected for 98.8% by weight) was then added to the solution in a medium vortex and left to mix until completely solubilized (see Table 14). The spray solution was passed through a 140 μm in-line filter during spraying. The viscosity of the spray solution was measured to be 23.86 cP.

Table 14. Formula I compound solution formulation weight

A mobile minor spray dryer was used, which was set up according to Table 15 and warmed for approximately 1 hour before spraying. The nozzle was allowed to equilibrate by spraying a washing solution (80:20 dichloromethane:methanol) before the active solution. The active solution of the compound of formula I was also sprayed according to the settings in Table 15.

Table 15. Mobile Minor Settings/Setpoints

Spraying approximately 20 kg of solution gave 1840.54 g of'wet' spray-dried intermediate (SDI). After spraying, SDI was dried under a nitrogen purge at 40° C. and -25 (Hg) vacuum in a shell vacuum oven at 10 scfh (4 days). Before putting the SDI in the oven and after drying, a sample was taken and analyzed for residual solvent through GC analysis to confirm that the SDI was dried. The GC results after 4 days of drying were within the target limits for both dichloromethane (<600 ppm, actual 65 ppm) and methanol (<3000 ppm, actual 9 ppm). The SDI was dried for a total of 86 hours. The dried SDI was analyzed for bulk/tap density and particle size distribution. The SDI was packaged in a double low density polyethylene bag, dried, and then sealed in a Mylar bag. 1742.90 g of the compound SDI of formula I was collected to give an 88% yield.

D. Spray solution and spray

A spray solution was prepared by adding methanol (62.0 kg) to the solution preparation container. The compound of formula I (5.9 kg) was added with mixing. HPMCAS-MG (5.9 kg) was added to the solution preparation vessel while mixing until the polymer and compound of formula I were completely solubilized. A slightly cloudy appearance was allowed. See Table 16.

Table 16. Formula I compound solution formulation weight

A BLD-200 spray dryer was used, and it was set according to Table 17. The washing solution (methanol) was sprayed before the active solution to allow the nozzles to equilibrate, and cooling water was passed through the spray dryer lid during processing. The active solution of the compound of formula I was sprayed according to the settings in Table 17.

Table 17. BLD-200 and dryer set points

After spraying, the SDI was dried in an oven at 40° C./15% relative humidity (21 hours). The GC result after 19 hours of drying was within the target limit for methanol (≤ 0.3% by weight, actually less than the limit of quantification), and 9.96 kg of the compound SDI of Formula I was collected to obtain an 84% yield.

Example 5: Pharmaceutical compositions containing spray-dried dispersions of compounds of formula I

A. Preparation of an intragranular composition containing a compound of formula I

The following ingredients were weighed in the following order and added to appropriately sized glass bottles: about half of microcrystalline cellulose, about half of mannitol or lactose, both SDI and disintegrant, the other half of mannitol or lactose and the remainder of microcrystalline cellulose. half. The ingredients were mixed on a turbula and then sieved through a 850 μm screen. The ingredients were again mixed on a turbula. Magnesium stearate was added and the mixture was mixed on a turbula. For large-scale implementation, a V-Blender was used instead of Turbula.

B. Granulation of the intragranular composition

The intragranular composition, also referred to as the first composition, was slugged on a single station tablet press using a Natoli 0.7" flat surface tool with a compressive force of 2200 PSI. The slugging procedure was repeated until the first composition was depleted. The slug was lightly crushed using a mortar and the composition was passed through a 1 mm sieve screen followed by a 850 μm sieve screen A piece of granules too large to pass through a 1 mm or 850 μm sieve screen was further ground in a mortar bowl. The process was repeated until all pieces had passed through the 850 μm sieve screen.

C. Examples of pharmaceutical compositions containing compounds of formula I

Pharmaceutical compositions can be prepared by combining the intragranular composition prepared as described above with an extragranular ingredient comprising components, lubricants and lubricants as listed in Table 18 to provide a pharmaceutical composition, which is in Example 6 below. It can be used to prepare compositions and tablets comprising various doses of a compound of formula I as further described in -8.

Table 18

Formula I pharmaceutical composition

*A is the first composition (intragranular blend).

Example 6: Preparation of 25 mg of compound pharmaceutical composition of formula I

The ingredients were weighed in the following order and added to a suitable sized container: half of Avicel® PH 200; Half of Partec® M200; All granules of the intragranular composition as prepared in Example 4; Xplotop®; Partec® M200; And Avicel® PH 200. This was mixed for 5 minutes at 32 RPM on a turbula and then sieved through a 850 μm screen. The mixture was further mixed for 5 minutes at 32 RPM on a turbula. Magnesium stearate was added and the mixture was mixed for 2 minutes at 32 RPM on a turbula. For large-scale implementation, a V-Blender was used instead of Turbula.

Table 19. 25 mg dosage form

*Contains 8% w/w Loxo-305 and 8% w/w HPMCAS-MG based on the total weight of the 25 mg dosage form.

Example 7: Preparation of 100 mg dosage form

The ingredients were weighed in the following order and added to a suitable sized container: about half of the granules of the first composition; Any Xplotop® or Syloid 244FP®; And the other half of the granules of the first composition as prepared in Example 4. This was mixed for 5 minutes at 32 RPM on a turbula and then sieved through a 850 μm screen. This was further mixed for 5 minutes at 32 RPM on a turbula. Magnesium stearate was added to the vessel and the mixture was mixed for 2 minutes at 32 RPM on a turbula. For large-scale implementation, a V-Blender was used instead of Turbula.

Table 20. 100 mg Formula I compound pharmaceutical composition

Example 8: Preparation of coated tablets

A 25 mg compound pharmaceutical composition of formula I was pressed on a tablet press and sprayed with a 15% Opadry/85% sterile water for injection (SWFI) mixture to prepare final coated tablets. The 25 mg tablets were 0.3437" rounds (Natoly).

A 100 mg compound pharmaceutical composition of formula I was pressed on a tablet press and sprayed with a 15% Opadry/85% sterile water for injection (SWFI) mixture to prepare final coated tablets. 100 mg tablets were 0.3750" rounds (Natoly).

The conditions of Table 21 were used to determine the dissolution of the tablets compared to the spray-dried intermediate of the compound of formula I and the crystalline compound of formula I. The results are presented in Figure 8.

Table 21. Dissolution conditions

Example 9: Comparison of in vivo pharmacokinetic parameters and bioavailability of spray-dried dispersions of compounds of formula I

A. Comparison with different polymers in spray-dried dispersions of compounds of formula I

In vivo rat bioavailability and pharmacokinetic studies were performed to investigate differences in bioavailability of suspensions of Sample 1, Sample 2 and Sample 3 from Example 4, Table 11.

Each formulation was suspended in 0.5% HPMC and given to 3 to 5 male Sprague Dolly rats at a dose of 400 mg/kg. Samples for pharmacokinetic (PK) analysis were collected at 0.5, 1, 2, 4, 8, 24, 48 and 72 hours after dosing. Blood samples were processed into plasma and stored frozen at -70° C. until the concentration of the compound of formula I was analyzed. The concentration of the compound of formula I in plasma was determined by reverse phase HPLC accompanied by mass spectrometry detection. The area under the curve of the compound of formula I (AUC) was calculated by the trapezoidal method over the time course of the study. ANOVA with Dunnett's correction for multiple comparisons was used to determine statistically significant differences from the reference formulation. In Table 22 the values of AUC and maximum concentration (Cmax) are reported as the mean ± standard deviation for each rat group.

Table 22. Concentration of compounds of formula I in plasma of Sprague Dawley rats

B. Comparison of compounds of formula I with different drug loads

In vivo rat bioavailability and pharmacokinetic studies were performed to obtain a 30%, 40% or 50% drug load of a dose of 400 mg/kg (7:3, 3:2 or 1:1 HPMCAS-MG, respectively: compound of formula I SDD) or a suspension of a 50% drug load at a dose of 100 mg/kg (1: 1 HPMCAS-MG: SDD of the compound of formula I) was investigated. Each formulation was suspended in 0.5% HPMC and served to 5 male Sprague Dolly rats. Samples for pharmacokinetic (PK) analysis were collected at 0.5, 1, 2, 4, 8, 24, 48 and 72 hours after dosing. Blood samples were processed into plasma and stored frozen at -70° C. until analysis of the compound of formula I concentration. The concentration of the compound of formula I in plasma was determined by reverse phase HPLC accompanied by mass spectrometry detection. The area under the curve of the compound of formula I (AUC) was calculated by the trapezoidal method over the time course of the study. In Table 23 the values of AUC and Cmax are reported as the mean ± standard deviation for each rat group.

Table 23. Concentration of compounds of formula I in plasma of Sprague Dawley rats

C. In vivo dog bioavailability and pharmacokinetic studies

In vivo dog bioavailability and pharmacokinetic studies were performed to determine the difference in bioavailability of the reference form (micronized compound of formula I) and SDD formulation of compound of formula I (1:1 HPMCAS-MG: compound of formula I). Investigated. The reference and SDD forms were suspended in 0.5% HPMC in water and given to 7 or 8 dogs at a dose of 30 mg/kg. Dogs were either fasted overnight prior to dosing (fasting) or fed canned food 45 minutes prior to dosing (feeding). Samples for pharmacokinetic (PK) analysis were collected 30 minutes, 1, 2, 4, 8, 24 and 48 hours after dosing. Blood samples were processed into plasma and stored frozen at -70° C. until analysis of the compound of formula I concentration. The concentration of the compound of formula I in plasma was determined by reverse phase HPLC accompanied by mass spectrometry detection. The area under the curve of the compound of formula I was calculated by the trapezoidal method over the time course of the study. ANOVA with Dunnett's correction for multiple comparisons was used to determine statistically significant differences from the reference formulation. In Table 24, the values of AUC and Cmax are reported as mean ± standard deviation for each dog group.

Table 24. Concentration of compounds of formula I in plasma of dogs

Example 10: Effect of Compound of Formula I and Ibrutinib Dose Response on Y223 Autophosphorylation in HEK293 Cells Stably Expressing BTK and BTK C481S

A HEK293 cell line stably expressing BTK wild type and mutant form C481S was generated using standard transfection methods. For evaluation of cell inhibitory potency, cells were grown in DMEM + 10% fetal bovine serum (FBS) + 1 μg/ml puromycin (complete growth medium) at 37° C. in a _{CO 2 incubator.} Cells were ^{harvested according to standard protocols using TRYPLE™} (Gibco#12604-013), counted, resuspended in complete growth medium, and 4 x 10^5 cells in a 6 well assay plate. /Well was added at 2 mL. Plates were incubated overnight at 37° C. under 5% CO _2. The next day, the cells were prepared as a 1:3 serial dilution of a 6-point dose curve with a final concentration starting at a maximum concentration of 300 nM and a constant DMSO concentration of 0.5% (v/v). Treated with Lutinib for 2 hours. Control wells contained 0.5% (v/v) DMSO alone (control without inhibition). All samples were tested in triplicate. After compound incubation, the growth medium was discarded, the cells were washed with DPBS (1X) (Gibco#14190-144), and 1 mL of Celtice containing 1x Holt phosphatase and protease inhibitor cocktail (Pierce # 78442). (CELLYTIC) ^TM M (Sigma # C2978) was dissolved. The plate was placed on ice for 1 hour with gentle stirring and stored at -80°C overnight. The next day, the cell lysate was put into a 1.5 mL tube, and purified by centrifugation at 16,000 xg for 10 minutes at 4°C. The supernatant was quantified by BCA (Pierce #23225) and stored at -80°C. Samples were sampled by Simple Western (Protein Simple) using anti-phospho-BTK (Y223) (Cell Signaling Technologies (CST) #5082) and anti-BTK (CST #8547). Analysis was performed (FIGS. 10A and 10B ). β-actin was used as a loading control and detected by regular Western blot using anti-β-actin antibody (CST # 4970). Simple Western results were analyzed with Compass software (Protein Simple). BTK Y223 phosphorylation signal was normalized to total BTK and IC ₅₀ values were calculated using a 4-parameter fit in GraphPad Prism 7.04 software. 10C and 10D show inhibitor concentration versus mean BTK Y223 phosphorylation signal with standard deviations for three independent assays. Compounds of formula I inhibited the autophosphorylation of BTK Y223 in both wild-type and C481S mutant proteins with IC _{50 values of 8.6 ± 0.3 nM and 8.8 ± 1.8 nM, respectively. Ibrutinib inhibited BTK wild type with an IC 50} of 5.7 ± 0.5 nM, and its activity against the C481S mutant could not be fitted to the _{IC 50 curve.}

Example 11: Inhibitory activity of compounds of formula I on BTK Y223 autophosphorylation and PLCγ2 Y1217 phosphorylation in Ramos RA1 cells

Ramos RA1 cells obtained from ATCC (CRL-1596) were grown in RPMI 1640 + 10% fetal bovine serum (FBS) at 37° C. in a CO2 incubator. Cells were harvested, washed with RPMI 1640 without FBS, and resuspended at a concentration of 1.2×10 7 cells/mL. 900 μL of cells/well were added to a 24-well plate, and 100 uL of 10x inhibitor stock was added. A 10x compound stock of formula I was prepared by performing a 1:3 serial dilution in 1% DMSO to a final concentration ranging from 900 nM to 0.41 nM in wells. Ibrutinib was tested at 100 and 300 nM, and the control wells had a final concentration of 0.01% DMSO. All samples were tested in triplicate. After 2 hours (depletion and administration), sodium orthovanadate was added to a final concentration of 200 μM, and incubated for another 30 minutes. Cells were then stimulated with 4 uL of goat F(ab')2 anti-human IgM (Jackson ImmunoResearch #109-006-129) for 5 minutes at room temperature, spin down, 5x Holt phosphatase and ^{Resuspended in 100 uL of Celtic TM} M (Sigma # C2978) containing a protease inhibitor cocktail (Pierce # 78442) and stored at -80°C. Lysates were quantified by BCA (Pierce # 23225) and analyzed by Simple Western (Protein Simple) using the following antibodies: anti-phospho-BTK (Y223) (Cell Signaling Technologies (CST) # 5082), Anti-BTK (CST # 8547), anti-phospho-PLCγ2 (Y1217) (CST 3871), anti-PLCγ2 (CST 3872) and anti-GAPDH (GAPDH refers to glyceraldehyde 3-phosphate dehydrogenase) (Novus # MAB5718-SP). GAPDH was used as a loading control. 11A shows a representative Western blot. Results were analyzed with Compass software (Protein Simple) and IC ₅₀ values were calculated with GraphPad Prism 7.04 software. BTK Y223 phosphorylation signal was normalized to total BTK, and PLCγ2 Y1217 phosphorylation was normalized to total PLCγ2. FIG. 11B shows the BTK Y223 phosphorylation signal versus inhibitor concentration, and FIG. 11C shows the PLCγ2 Y1217 phosphorylation signal versus inhibitor concentration. The compound of formula I inhibited the autophosphorylation of BTK Y223 with _{an IC 50} of 3.2 ± 0.6 nM, and inhibited the phosphorylation of PLCγ2 Y1217 with _{an IC 50 of 8.2 nM ± 4.3.}

Example 12: Effect of compounds of formula I on BTK-dependent cell proliferation in human TMD8 diffuse versus B-cell lymphoma cell lines

TMD8 cells were maintained in RPMI 1640 with 10% fetal bovine serum (FCS), 1% Glutamax™, non-essential amino acids and 1 mM sodium pyruvate (Gibco catalog #31870-025). Cells were harvested by centrifugation (5 min, 1200 rpm) before reaching a concentration of 3×10 ^{6 cells/mL.} The medium was removed, and the cell pellet was resuspended in fresh medium, and then counted with a cellometer (Nexcelom). TMD8 cells were seeded at 5 ^{×10 4} cells/mL in 20 mL of culture medium in a T75 culture flask and maintained at 37° C. under _{5% CO 2.}

The antiproliferative activity of compounds of formula I by TMD8 cells was evaluated by the addition of increasing concentrations of inhibitors from 0.1 to 1,000 nM. Dose-dependent inhibition was observed by real-time evaluation of the TMD8 confluence growth rate. Individual curves for the concentration of each compound of Formula I are shown in Figure 12A. Quantification of the area under the curve (AUC) for each individual curve _{allowed the determination of the IC 50} 2.33 nM of the compound of formula I for TMD8 proliferation (FIG. 12B ). These data indicate that the compound of formula I inhibited the proliferation of TMD8 cells in a dose dependent manner.

Example 13: Inhibition of tumor growth of compounds of formula I in male NOD SCID mice transplanted with OCI-Ly10 xenografts

A total of 65 male NOD-SCIO mice were used in the study. At the start of the study, animals were 6-8 weeks old and weighed approximately 21-27 g. Animals were housed in IVC cages (up to 5 per cage) and individual mice were identified by tail markings. All animals were given free access to standard certified commercial diet and sanitary water during the study. The holding chamber was maintained under standard conditions: 20-24° C., 40-70% humidity and a 12 hour light/dark cycle. Animals were randomly assigned to treatment groups. OCI-Ly10 cells were implanted subcutaneously into the lateral abdomen of male NOD SCID mice and allowed to grow to a volume of ^{approximately 150-200 mm 3.} Dosages were prepared by stirring the compound of formula (I) or ibrutinib until wet, sonicating for 30 minutes, and stirring overnight at room temperature between dosing periods. The formulation used was 0.5% hydroxypropyl methylcellulose. The dose volume was 10 mL/kg. The dose of individual animals was calculated from the body weight recorded on the day of dosing. Animals were administered for 28 days. Animal body weight and health observations were recorded daily for the duration of dosing.

Tumor volume was measured three times per week during the study. Compounds of formula I at both 10 mg/kg and 50 mg/kg BID caused inhibition of tumor growth during the administration period. 13A shows tumor growth with tumor volume expressed as mean±SEM for mice administered orally with the indicated vehicle or inhibitor. Inhibition of tumor growth with the compound of formula I was maintained even after administration was stopped (FIG. 13B ). Treatment with compounds of formula I of both 10 and 50 mg/kg BID produced significantly smaller tumors than tumors from animals treated with ibrutinib (p=0.0008 and <0.0001, respectively, Turkey post-test. Accompanying ANOVA). 13C shows normalized body weight values over the course of treatment expressed as mean±SEM.

Example 14: Tumor growth in human xenograft diffuse versus B cell lymphoma model of SCID mice

Cell culture

Human diffuse versus B cell lymphoma TMD8 cells were maintained in suspension in RPMI 1640 containing 10% fetal bovine serum (FCS) and 1% glutamax. Cells were transferred to 50 mL Falcon tubes and centrifuged at 1200 rpm for 5 minutes. The supernatant was removed, the cell pellet was resuspended in PBS, and then mixed with Matrigel (1/1, v/v). The cell suspension: Matrigel mixture was kept on ice until sc injection (250 μL/mouse) at a final target cell concentration ^{of 40×10 6 cells/mL to keep the Matrigel solution in a liquid state.}

Animal line

Animals were 9 week old female BalB/c mice on the day of injection. Mice were housed in individual ventilated cage racks supplied with HEPA filtered air, and all substances in contact with immunodeficient animals were steam sterilized. This included cage, bedding, water and feed. Animal indoor conditions were set as follows. The temperature was 22±2°C, and the relative humidity was 50±10%. The light/dark cycle was 12 hours/12 hours, and the air change rate was 12 to 15 cycles/hour of filtered 100% fresh air. All animals had free access to sterilized water and irradiated control food (reference A04CSafe, French Augie).

Preparation of compounds of formula I

Compounds of formula I were formulated in methylcellulose/Tween 80/water (0.6%/0.5%/98.5%; w/w/v). The vehicle for administration of the control group was methylcellulose/Tween 80/water (0.6%/0.5%/98.5%; w/w/v), 10 mL/kg. 151.4 mg of compound of formula I was weighed and formulated with 50.4 mL of vehicle to give a solution of 3 mg/mL of free base. For the preparation of a 1 mg/mL suspension, 50.1 mg of the compound of formula I was weighed and solubilized in 50.1 mL of vehicle.

Tumor cell injection and tumor growth monitoring

Female SCID mice were anesthetized by inhalation of ISOFLURANE® (5%, O ₂ /mixed with air, 2 L/min). The injection area (lower flank) was shaved. After washing the skin and disinfecting with chlorhexidine, the TMD8 cell suspension was injected. A volume of 250 μL of cell suspension ( ^{cells in PBS mixed with Matrigel®, corresponding to 10×10 6} cells) was injected sc using a 30-gauge needle. After a few seconds, the needle was removed and the injection area was washed with chlorhexidine. Subsequently, the mice were stored in the postoperative chamber at 28° C. until complete recovery.

Tumor width and length were measured with a digital caliper. Tumor volume (mm ³ ) was calculated by the following formula: volume = 0.52 x (width) ² x length/2 (width and length are measured in mm). When the tumor volume reached an average size of 150 mm ³ (14 days after cell injection in this study), mice were divided into three separate experimental groups to make a homogeneous group with close mean tumor volume ± SEM. Mice body weight was examined daily, and tumor volume was examined 2-3 times/week. A summary of the study groups for treatment is shown in Table 25. 14A shows tumor volumes expressed as days after cell injection versus mean±SEM for the three groups. The last administration was performed on day 28 after cell injection, corresponding to the 14 day period of chronic administration.

Table 25. Summary of study groups for treatment

Tumors were collected from each mouse on day 28 after cell injection. Mice were anesthetized by inhalation of Isoflurane® (5%, O ₂ /mixed with air, 2 L/min). The tumor was weighed. 14B shows tumor weight at the end of the study expressed as mean±SEM for the 3 groups. Tumor weight statistical analysis between each group was determined by one-way ANOVA, and by two-way ANOVA with repeated measurements for mouse weight and tumor volume monitoring, followed by Dunnett's test. The difference was considered significant with a P value <0.05. 14C shows the number of days after cell injection versus mouse body weight expressed as mean±SEM for the three groups.

Chronic oral BID administration of the compound of formula I at 10 and 30 mg/kg for 14 days was well tolerated. At higher doses, treatment significantly reduced the growth of TMD8 tumor xenografts in SCID mice (35% and 87% TGI compared to vehicle treatment group, respectively). At the endpoint, a strong inhibitory effect on tumor growth was confirmed by treatment with 30 mg/kg of a compound of formula I twice a day by tumor weight.

Example 15: Comparison of bioavailability and pharmacokinetics in dogs of crystalline compounds of formula I in suspension and spray-dried dispersions of compounds of formula I in suspension

A. Pharmacokinetics of compounds of formula I administered as crystalline compounds of formula I in suspension

The crystalline compound of formula I was prepared as a suspension in 6 mg/mL of 0.5% hydroxypropylmethyl cellulose (HPMC) for the administration of 30 mg/kg; Correction factors for the dosage formulation were not used. Three male and five female beagle dogs were administered a single PO gavage dose of 30 mg/kg of a compound of formula I formulated as a suspension in 0.5% HPMC. After the 7-day dosing period between the dosing period/feeding conditions, all animals were administered a suspension of the crystalline compound of formula I in the fed and fasted state. For both feeding conditions, access to food was removed at least 12 hours prior to dose administration. In crossover #1, 6 dogs were fed a mixture of canned and dried foods approximately 45 minutes prior to dose administration (Group 1), and 2 dogs were administered a compound of formula I on an empty stomach, 4 hours after administration. It was fed (Group 2). At crossover #2, two dogs administered the compound of formula I in the fasting state at crossover #1 were fed a mixture of canned and dried foods approximately 45 minutes prior to dose administration (group 3), and at crossover #1 Five dogs administered the compound of formula I in the feeding state were administered the compound of formula I in the fasting state, and fed 4 hours after the administration (group 4) (Table 26). The same 3 males and 3 females were assigned to groups 1 and 4 (with the exception of 1 female, assigned to group 1 but not included in group 4), and the same 2 females were assigned to groups 2 and 3 Assigned.

Table 26. Summary of study design

Blood samples were collected via jugular vein into EDTA blood collection tubes after PO administration at 0 (pre-dose), 0.5, 1, 2, 4, 8, 24 and 48 hours. Samples were centrifuged at 3500 rpm for 10 minutes at 4-8° C., and plasma fractions were stored frozen at -70° C. prior to bioanalytical analysis. After protein precipitation with acetonitrile, the concentration of the compound of formula I in dog plasma was determined by LC-MS/MS. Individual plasma concentration profiles over time and non-compartmental pharmacokinetic parameters of compounds of formula I were calculated by conventional methods using Microsoft Excel.

B. Pharmacokinetics of compounds of formula I administered as spray-dried dispersions of compounds of formula I in suspension

Spray-dried intermediate (SDI) of a compound of formula I (1:1 HPMCAS-MG: compound of formula I) is 6 mg/mL of 0.5% hydroxypropylmethyl cellulose (HPMC) for the administration of 30 mg/kg Prepared as a suspension in Four male and four female beagle dogs were administered a single PO gavage dose of 30 mg/kg of 50% SDI of a compound of formula I formulated as a suspension in 0.5% HPMC. After the 7-day dosing period between the dosing period/feeding conditions, all animals were administered the test article in the fed and fasted state. For both feeding conditions, access to food was removed at least 12 hours prior to dose administration. In crossover #1, 4 dogs were fed a mixture of canned and dried foods approximately 45 minutes prior to dose administration (Group 1), and 4 dogs were administered a compound of formula I on an empty stomach, 4 hours after administration. It was fed (Group 2). At crossover #2, 4 dogs fasting at crossover #1 were fed a mixture of canned and dried foods approximately 45 minutes prior to dose administration (group 4), and 4 dogs fasted at crossover #1 on an empty stomach. In the state, the compound of formula I was administered, and fed 4 hours after the administration (group 3) (Table 27). The same two males and two females were assigned to groups 1 and 3, and the same two males and two females were assigned to groups 2 and 4.

Table 27. Summary of study design

Blood samples were collected via jugular vein into EDTA blood collection tubes after PO administration at 0 (pre-dose), 0.5, 1, 2, 4, 8, 24 and 48 hours. Samples were centrifuged at 3500 rpm for 10 minutes at 4-8° C., and plasma fractions were stored frozen at -70° C. prior to bioanalytical analysis. After protein precipitation with acetonitrile, the concentration of the compound of formula I in dog plasma was determined by LC-MS/MS. Individual plasma concentration profiles over time and non-compartmental pharmacokinetic parameters of compounds of formula I were calculated by conventional methods using Microsoft Excel.

C. Pharmacokinetics of compounds of formula I administered as tablets of spray-dried dispersions of compounds of formula I

Each animal was administered 3 tablets for a dose of 300 mg/dog (approximately 30 mg/kg). The tablet contained 50% SDI of the compound of formula I. Four male and four female beagle dogs were administered a single PO gavage dose of three 100-mg Formula I compound tablets. After the 7-day dosing period between the dosing period/feeding conditions, all animals were administered the test article in the fed and fasted state. For both feeding conditions, access to food was removed at least 12 hours prior to dose administration. In crossover #1, 4 dogs were fed a mixture of canned and dried foods approximately 45 minutes prior to dose administration (Group 1), and 4 dogs were administered a compound of formula I on an empty stomach, 4 hours after administration. It was fed (Group 2). In crossover #2, 4 dogs administered under fasting conditions in crossover #1 were fed a mixture of canned and dry food approximately 45 minutes prior to dose administration (group 4), and administered under fasting conditions in crossover #1. Four dogs were administered the compound of formula I on an empty stomach, and fed 4 hours after the administration (group 3) (Table 28). The same two males and two females were assigned to groups 1 and 3, and the same two males and two females were assigned to groups 2 and 4.

Table 28. Summary of study design

Blood samples were collected via jugular vein into EDTA blood collection tubes after PO administration at 0 (pre-dose), 0.5, 1, 2, 4, 8, 24 and 48 hours. Samples were centrifuged at 3500 rpm for 10 minutes at 4-8° C., and plasma fractions were stored frozen at -70° C. prior to bioanalytical analysis. After protein precipitation with acetonitrile, the concentration of the compound of formula I in dog plasma was determined by LC-MS/MS. Individual plasma concentration profiles over time and non-compartmental pharmacokinetic parameters of compounds of formula I were calculated by conventional methods using Microsoft Excel.

D. Summary of the results of Parts A, B and C

Table 29. Summary of the results of Parts A, B and C

*The fold change is the feeding/fasting ratio.

_{**Bioavailability (F) is based on AUC 0-inf} 10700 ng*h/mL in dogs given a 2-mg/kg IV dose of the stable-labeled compound of Formula I. Bioavailability is calculated based on _{AUC 0-t} after oral administration.

FIG. 15A shows the concentration of compound of formula I in plasma for fed or fasting dogs fed individuals administered crystalline compound of formula I in suspension in Part A. FIG. Average formula I compound exposure (Cmax and AUC0-t) was 5 to 7 times greater in feeding animals compared to fasting animals.

FIG. 15B shows the concentration of the compound of formula I in plasma for fed or fasting dogs fed individuals administered 50% SDI of the compound of formula I in Part B. FIG. There was no obvious difference in the exposure of the compound of formula I after administration of 50% SDI of the compound of formula I to feeding or fasting animals.

Other aspects of the invention are described below.

The present invention provides a spray-dried dispersion comprising a compound of formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, and a hypromellose acetate succinate (HPMCAS) polymer. In one embodiment the ratio of the compound of Formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, to the HPMCAS polymer is from about 1:4 to about 4:1. In another embodiment the ratio of the compound of Formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof to the HPMCAS polymer is about 1:1.

The present invention is a method of preparing a spray-dried dispersion as described herein, wherein a compound of formula (I) or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof is dissolved in one or more organic solvents prior to spray-drying. Provides. In one embodiment, the compound of formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, is dissolved in 80:20 dichloromethane:methanol prior to spray-drying. In one embodiment, the compound of formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, is Form A of the compound of formula I.

The present invention comprises a first composition comprising a spray-dried dispersion and one or more pharmaceutical excipients, wherein the spray-dried dispersion is an HPMCAS polymer and a compound of formula I or a pharmaceutically acceptable salt thereof, amorphous or It provides a pharmaceutical composition comprising a polymorphic form. The ratio of the compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof to the HPMCAS polymer in the spray-dried dispersion is from about 1:4 to about 4:1. Alternatively, the ratio of the compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof to the HPMCAS polymer in the spray-dried dispersion is about 1:1. In one embodiment, the spray-dried dispersion is present in an amount of about 20% to about 75% w/w of the first composition. In one embodiment, the spray-dried dispersion is present in an amount of about 30% to about 60% w/w of the first composition. In one embodiment, the spray-dried dispersion is present in an amount of about 40% to about 50% w/w of the first composition. In one embodiment, the spray-dried dispersion is present in an amount of about 45% w/w of the first composition.

In one embodiment, the pharmaceutical excipient is selected from the group consisting of fillers, lubricants and combinations thereof. The filler may be present in an amount of about 25% to about 80% w/w of the first composition. In one embodiment, the filler is present in an amount of about 45% to about 65% w/w of the first composition. In one embodiment, the filler is present in an amount of about 55% w/w of the first composition. In one embodiment, the filler is selected from the group consisting of saccharides, gelatin, synthetic polymers, or combinations thereof. In one embodiment, the filler is sucrose, lactose, microcrystalline cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, starch, xylitol, sorbitol, mannitol, polyvinylpyrrolidone, polyethylene. Glycol, polyvinyl alcohol, polymethacrylate, poloxamer, magnesium stearate, calcium stearate, sodium stearate, stearic acid, hydrogenated vegetable oil, mineral oil, sodium lauryl sulfate, magnesium lauryl sulfate, glyceryl Palmitostearate, sodium benzoate, sodium stearyl fumarate, colloidal silicon dioxide, sodium benzoate, sodium oleate, sodium acetate and combinations thereof.

In one embodiment, the filler is a binder, a disintegrant, or a combination thereof. In one embodiment, the binder is present in an amount of about 30% to about 80% w/w of the first composition. In one embodiment, the binder is present in an amount of about 40% to about 60% w/w of the first composition. In one embodiment, the binder is present in an amount of about 52% w/w of the first composition. In one embodiment, the binder is microcrystalline cellulose, cellulose ether, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxy methyl cellulose starch, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, mannitol, xylitol, sorbitol , Lactose, sucrose, sorbitol, gelatin, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, polymethacrylate, and combinations thereof. In one embodiment, the binder is microcrystalline cellulose, mannitol, or a combination thereof. In one embodiment, the microcrystalline cellulose is present in an amount of about 5% to about 55% w/w of the first composition. In one embodiment, the microcrystalline cellulose is present in an amount of about 10% to about 40% w/w of the first composition. In one embodiment, the microcrystalline cellulose is present in an amount of about 20% to about 30% w/w of the first composition. In one embodiment, the microcrystalline cellulose is present in an amount of about 26% w/w of the first composition.

In one embodiment, mannitol is present in an amount of about 5% to about 55% w/w of the first composition. In one embodiment, mannitol is present in an amount of about 10% to about 40% w/w of the first composition. In one embodiment, mannitol is present in an amount of about 20% to about 30% w/w of the first composition. In one embodiment, mannitol is present in an amount of about 26% w/w of the first composition.

In one embodiment, the disintegrant is present in an amount of about 0.5% to about 5% w/w of the first composition. In one embodiment, the disintegrant is present in an amount of about 1.5% to about 3.5% w/w of the first composition. In one embodiment, the disintegrant is present in an amount of about 2.5% w/w of the first composition. In one embodiment, the disintegrant is selected from the group consisting of sodium starch glycolate, alginic acid, sodium alginate, ion exchange resins, and combinations thereof. In one embodiment, the disintegrant is sodium starch glycolate.

In one embodiment, the lubricant is present in an amount of about 0.05% to about 2.5% w/w of the first composition. In one embodiment, the lubricant is present in an amount of about 0.1% to about 1% w/w of the first composition. In one embodiment, the lubricant is present in an amount of about 0.25% w/w of the first composition. In one embodiment, the lubricant is magnesium stearate, calcium stearate, sodium stearate, stearic acid, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulfate, glyceryl palmitostearate. , Sodium benzoate, sodium stearyl fumarate, colloidal silicon dioxide, sodium benzoate, sodium oleate, sodium acetate, and combinations thereof. In one embodiment, the lubricant is magnesium stearate.

In one embodiment, the spray-dried dispersion is present in an amount of about 20% to about 75% w/w of the first composition, and the filler is in an amount of about 25% to about 80% w/w of the first composition. And the lubricant is present in an amount of about 0.05% to about 2% w/w of the first composition. In one embodiment, the spray-dried dispersion is present in an amount of about 45% w/w of the first composition, the filler is present in an amount of about 55% w/w of the first composition, and the lubricant is It is present in an amount of about 0.25% w/w of the composition. In one embodiment, the spray-dried dispersion is present in an amount of about 40% to about 50% w/w of the first composition, and the microcrystalline cellulose is about 20% to about 30% w/w of the first composition. And mannitol is present in an amount of about 20% to about 30% w/w of the first composition, and sodium starch glycolate is present in an amount of about 0.5% to about 5% w/w of the first composition. And magnesium stearate is present in an amount of about 0.05% to about 2% w/w of the first composition. In one embodiment, the spray-dried dispersion and pharmaceutical excipient are blended. In one embodiment, the first composition is granulated. In one embodiment, the first composition is granulated by roller compaction.

In one embodiment, the first composition is present in an amount of about 15% to about 99% w/w of the total composition. In one embodiment, the one or more pharmaceutical excipients are selected from the group consisting of fillers, lubricants, and combinations thereof. In one embodiment, the lubricant is present in an amount of about 0.05% to about 2% w/w of the total composition. In one embodiment, the lubricant is present in an amount of about 0.1% to about 0.8% w/w of the total composition. In one embodiment, the lubricant is present in an amount of about 0.3% w/w of the total composition. In one embodiment, the lubricant is magnesium stearate, calcium stearate, sodium stearate, stearic acid, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulfate, glyceryl palmitostearate. , Sodium benzoate, sodium stearyl fumarate, colloidal silicon dioxide, sodium benzoate, sodium oleate, sodium acetate, and combinations thereof. In one embodiment, the lubricant is magnesium stearate. In one embodiment, the filler is present in an amount of about 1% to about 85% w/w of the total composition. In one embodiment, the filler is sucrose, lactose, microcrystalline cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, starch, xylitol, sorbitol, mannitol, polyvinylpyrrolidone, polyethylene. Glycol, polyvinyl alcohol, polymethacrylate, poloxamer, magnesium stearate, calcium stearate, sodium stearate, stearic acid, hydrogenated vegetable oil, mineral oil, sodium lauryl sulfate, magnesium lauryl sulfate, glyceryl Palmitostearate, sodium benzoate, sodium stearyl fumarate, colloidal silicon dioxide, sodium benzoate, sodium oleate, sodium acetate and combinations thereof. In one embodiment, the filler is a binder, a disintegrant, or a combination thereof. In one embodiment, the disintegrant is present in an amount of about 0.5% to about 5% w/w of the total composition. In one embodiment, the disintegrant is present in an amount of about 2.5% w/w of the total composition. In one embodiment, the disintegrant is selected from the group consisting of sodium starch glycolate, alginic acid, sodium alginate, ion exchange resins, and combinations thereof. In one embodiment, the disintegrant is sodium starch glycolate. In one embodiment, the first composition is present in an amount of about 90% to about 99% w/w of the total composition. In one embodiment, the first composition is present in an amount of about 97% w/w of the total composition. In one embodiment, the first composition is present in an amount of about 15% to about 60% w/w of the total composition. In one embodiment, the first composition is present in an amount of about 30% to about 40% w/w of the total composition. In one embodiment, the first composition is present in an amount of about 35% w/w of the total composition. In one embodiment, the binder is present in an amount of about 40% to about 85% w/w of the total composition. In one embodiment, the binder is present in an amount of about 55% to about 75% w/w of the total composition. In one embodiment, the binder is microcrystalline cellulose, cellulose ether, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxy methyl cellulose starch, cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, mannitol, xylitol, Sorbitol, lactose, sucrose, sorbitol, gelatin, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, polymethacrylate, and combinations thereof. In one embodiment, the binder is microcrystalline cellulose, mannitol, or a combination thereof. In one embodiment, the microcrystalline cellulose is present in an amount of about 25% to about 35% w/w of the total composition. In one embodiment, microcrystalline cellulose is present in an amount of about 31% w/w of the total composition. In one embodiment, mannitol is present in an amount of about 25% to about 35% w/w of the total composition. In one embodiment, mannitol is present in an amount of about 31% w/w of the total composition. In one embodiment, the first composition is blended with a pharmaceutical excipient. In one embodiment, the pharmaceutical composition is co-milled. In one embodiment, the pharmaceutical composition is formulated as a tablet. In one embodiment, the compound of Formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, is present in an amount of about 10 mg to about 50 mg. In one embodiment, the compound of Formula I, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, is present in an amount of about 25 mg to about 220 mg.

The present invention is (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane- 2-yl)-1H-pyrazole-4-carboxamide; HPMCAS polymer; And one or more pharmaceutical excipients. In one embodiment, in one embodiment, in the pharmaceutical composition of claim 83, the one or more pharmaceutical excipients are selected from the group consisting of fillers, lubricants, and combinations thereof. In one embodiment, the filler is sucrose, lactose, microcrystalline cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, starch, xylitol, sorbitol, mannitol, polyvinylpyrrolidone, polyethylene. Glycol, polyvinyl alcohol, polymethacrylate, magnesium stearate, calcium stearate, sodium stearate, stearic acid, hydrogenated vegetable oil, mineral oil, sodium lauryl sulfate, magnesium lauryl sulfate, glyceryl palmitostea Rate, sodium benzoate, sodium stearyl fumarate, colloidal silicon dioxide, sodium benzoate, sodium oleate, sodium acetate, and combinations thereof. In one embodiment, the lubricant is magnesium stearate, calcium stearate, sodium stearate, stearic acid, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulfate, glyceryl palmitostearate. , Sodium benzoate, sodium stearyl fumarate, colloidal silicon dioxide, sodium benzoate, sodium oleate, sodium acetate, and combinations thereof. In one embodiment, the composition is (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-tri Fluoropropan-2-yl)-1H-pyrazole-4-carboxamide; HPMCAS polymer; Microcrystalline cellulose; Mannitol; Sodium starch glycolate; And magnesium stearate. In one embodiment, the composition is (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzami) present in an amount of about 5% to about 30% w/w of the composition. Figure)methyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide; HPMCAS polymer present in an amount from about 5% to about 30% w/w of the composition; Microcrystalline cellulose present in an amount from about 30% to about 60% w/w of the composition; Mannitol present in an amount from about 30% to about 60% w/w of the composition; Sodium starch glycolate present in an amount from about 0.5% to about 5% w/w of the composition; And magnesium stearate present in an amount of about 0.05% to about 2% w/w of the composition. In one embodiment, the composition is (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl) present in an amount of about 8% w/w of the composition. Phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide; HPMCAS polymer present in an amount of about 8% w/w of the composition; Microcrystalline cellulose present in an amount of about 40% w/w of the composition; Mannitol present in an amount of about 40% w/w of the composition; Sodium starch glycolate present in an amount of about 3.5% w/w of the composition; And magnesium stearate present in an amount of about 0.3% w/w of the composition. In one embodiment, the composition is (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzami) present in an amount of about 10% to about 30% w/w of the composition. Figure)methyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide; HPMCAS polymer present in an amount from about 10% to about 30% w/w of the composition; Microcrystalline cellulose present in an amount from about 20% to about 30% w/w of the composition; Mannitol present in an amount from about 20% to about 30% w/w of the composition; Sodium starch glycolate present in an amount from about 2% to about 8% w/w of the composition; And magnesium stearate present in an amount of about 0.05% to about 2% w/w of the composition. In one embodiment, the composition is (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl) present in an amount of about 22% w/w of the composition. Phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide; HPMCAS polymer present in an amount of about 22% w/w of the composition; Microcrystalline cellulose present in an amount of about 25% w/w of the composition; Mannitol present in an amount of about 25% w/w of the composition; Sodium starch glycolate present in an amount of about 5% w/w of the composition; And magnesium stearate present in an amount of about 0.5% w/w of the composition. In one embodiment, the pharmaceutical composition is formulated as a tablet. In one embodiment, the tablet is coated.

The present invention is (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane- 2-yl)-1H-pyrazole-4-carboxamide, HPMCAS polymer and organic solvent are mixed to form a mixture; Spray-drying the mixture to form a spray-dried dispersion; And granulating the spray-dried dispersion to form a first composition. In one embodiment, the organic solvent is a mixture of dichloromethane and methanol. In one embodiment, the organic solvent is 80:20 dichloromethane:methanol. In one embodiment, the spray-dried dispersion is granulated after blending with one or more pharmaceutical excipients. In one embodiment, the spray-dried dispersion is granulated after drying in an oven. In one embodiment, the spray-dried dispersion is granulated after blending with one or more pharmaceutical excipients. In one embodiment, the spray-dried dispersion is granulated by roller compaction. In one embodiment, the first composition is blended with one or more pharmaceutical excipients. In one embodiment, the first composition is co-milled. In one embodiment, the first composition is compressed into tablets. In one embodiment, the tablet is coated. In one embodiment, the coating comprises a polymer, a plasticizer, a pigment, or a combination thereof. In one embodiment, (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1, in a spray-dried dispersion The ratio of 1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide to HPMCAS polymer is from about 1:4 to about 4:1. In one embodiment, (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1, in a spray-dried dispersion The ratio of 1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide to HPMCAS polymer is about 1:1.

The present invention provides crystalline forms of compounds of formula I having the formula

In one embodiment, the crystalline form is Form A characterized by having an X-ray powder diffraction (XRPD) pattern comprising peaks at °2θ values of 15.8±0.2, 16.2±0.2, and 11.9±0.2.

In one embodiment, the crystalline form is characterized as having an X-ray powder diffraction (XRPD) pattern comprising peaks at °2θ values of 15.8±0.2, 16.2±0.2, 11.9±0.2, 19.0±0.2, and 18.3±0.2. It is form A. In one embodiment, the crystalline form is an X-ray powder diffraction (X-ray powder diffraction) comprising peaks at °2θ values of 15.8±0.2, 16.2±0.2, 11.9±0.2, 19.0±0.2, 18.3±0.2, 23.8±0.2, and 20.5±0.2. XRPD) is a form A characterized by having a pattern. In one embodiment, the crystalline form is 15.8±0.2, 16.2±0.2, 11.9±0.2, 19.0±0.2, 18.3±0.2, 23.8±0.2, 20.5±0.2, 25.7±0.2, 20.1±0.2, and 9.5±0.2 of °2θ. Form A characterized by having an X-ray powder diffraction (XRPD) pattern comprising peaks in values. In one embodiment, the crystalline form is 15.8±0.2, 16.2±0.2, 11.9±0.2, 19.0±0.2, 18.3±0.2, 23.8±0.2, 20.5±0.2, 25.7±0.2, 20.1±0.2, 9.5±0.2, 25.0± Form A characterized by having an X-ray powder diffraction (XRPD) pattern comprising peaks at values of °2θ of 0.2 and 11.1±0.2. In one embodiment, the crystalline form is Form A and has an XRPD pattern substantially as shown in FIG. 4A. In one embodiment, the crystalline form is Form A and has a differential scanning calorimetry (DSC) curve comprising an endotherm with an onset temperature of about 185°C. In one embodiment, the crystalline form is Form A and has a DSC thermogram substantially as shown in FIG. 4C.

The present invention provides a solid oral pharmaceutical composition comprising a pharmaceutical excipient and a crystalline form. In one embodiment, the pharmaceutical composition is prepared by mixing a crystalline form and a pharmaceutical excipient.

The present invention provides a method of preparing a solid oral pharmaceutical composition comprising the step of mixing a crystalline form as described herein and a pharmaceutical excipient. In one embodiment, a liquid pharmaceutical composition is prepared by mixing a crystalline form as described herein and a pharmaceutical excipient. In one embodiment, the method comprises mixing the crystalline form and the pharmaceutical excipient.

The present invention provides a method of treating cancer in a subject in need thereof comprising administering a spray-dried dispersion, pharmaceutical composition or a therapeutically effective amount of a compound of formula I. In one embodiment, the cancer is a BTK-associated cancer. In one embodiment, the method comprises the steps of: (a) detecting a dysregulation of the expression or activity or level of a BTK gene, a BTK kinase, or any of these; And (b) administering to the subject a spray-dried dispersion as described herein, a pharmaceutical composition as described herein, or a therapeutically effective amount of a compound as described herein. In one embodiment, the method comprises administering to the subject a spray-dried dispersion, pharmaceutical composition, or a therapeutically effective amount of a compound of formula I to the subject identified or diagnosed as having a BTK-associated cancer. In one embodiment, the method comprises detecting a dysregulation of the expression or activity or level of a BTK gene, a BTK kinase, or any of these; And administering a spray-dried dispersion, pharmaceutical composition, or a therapeutically effective amount of a compound of Formula I to a subject determined to have BTK-associated cancer. In one embodiment, the method is a spray-dried dispersion, pharmaceutical composition, or treatment to a subject with a clinical record indicating that the subject has dysregulation of the expression or activity or level of the BTK gene, BTK kinase, or any of these. And administering an effective amount of a compound of formula (I).

In one embodiment, the method comprises administering to the subject in need thereof a spray-dried dispersion, pharmaceutical composition, or a therapeutically effective amount of a compound of formula (I). Includes restraint. In one embodiment, the cancer is a BTK-associated cancer.

The present invention provides for a subject comprising the step of selecting a treatment comprising administration of a spray-dried dispersion, pharmaceutical composition or a therapeutically effective amount of a compound of the formula to a subject identified or diagnosed with BTK-associated cancer. Provides a way to choose treatment. In one embodiment, the method comprises detecting a dysregulation of the expression or activity or level of a BTK gene, a BTK kinase, or any of these in the subject; And selecting a treatment for the subject comprising administration of a spray-dried dispersion, pharmaceutical composition or a therapeutically effective amount of formula (I).

In one embodiment, the method comprises identifying a subject having a BTK-associated cancer; And selecting a subject for treatment comprising administration of a spray-dried dispersion, pharmaceutical composition or a therapeutically effective amount of a compound of formula I. In one embodiment, the method comprises detecting dysregulation of the expression or activity or level of a BTK gene, BTK kinase, or any of these in a subject having cancer; And selecting a subject for treatment comprising administration of a spray-dried dispersion, pharmaceutical composition or a therapeutically effective amount of a compound of formula I. In one embodiment, the method comprises determining whether the cancer in the subject is a BTK-associated cancer, which is at the expression or activity or level of the BTK gene, BTK kinase protein, or any of them in a sample from the subject. And performing an assay to detect dysregulation of. In one embodiment, the method comprises obtaining a sample from the subject. The sample can be a biopsy sample. In one embodiment, the assay is selected from the group consisting of sequencing, immunohistochemistry, immunoblot, enzyme-linked immunosorbent assay, and fluorescence in situ hybridization (FISH). In one embodiment, the FISH is a degraded FISH assay. In one embodiment, sequencing is pyrosequencing or next-generation sequencing.

In one embodiment, the dysregulation at the expression or activity or level of a BTK gene, a BTK kinase protein, or any of these, is the expression or activity or level of a BCR signaling pathway gene, a BCR signaling pathway protein, or any of these. It is the result of an abnormality of regulation in In one embodiment, the BCR signaling pathway gene or BCR signaling pathway protein is selected from the group consisting of Cyclin-D1, CARD11, CD79B, CD79A, MYD88, and combinations thereof. In one embodiment, the dysregulation in the expression or activity or level of a BCR signaling pathway gene, a BCR signaling pathway protein, or any one of them is the result of one or more genetic alterations. In one embodiment, the one or more genetic alterations consist of chromosome translocation t(11;14)(q13;q32), deletion of chromosome region 17p13, deletion of chromosome region 11q23, deletion of chromosome region 13q14 and trisomy of chromosome 12. Is selected from the group. In one embodiment, the one or more genetic alterations are one or more point mutations in a gene encoding a BCR signaling pathway protein. In one embodiment, at least one point mutation in the gene encoding the BCR signaling pathway protein results in translation of the BCR signaling pathway protein with at least one amino acid substitution, wherein the BCR signaling pathway protein is CARD11, CD79B, CD79A, MYD88 and combinations thereof. In one embodiment, BCR signaling pathway protein with one or more point mutations to the amino acid positions in the genes encoding: MYD88 results in a translation of BCR signaling pathway protein comprising the amino acid substitution at least one of the at least one of ^L265 . In one embodiment, the amino acid substitution is MYD88 ^L265P . In one embodiment, the dysregulation in the expression or activity or level of the BTK gene, BTK kinase protein, or any of these is one or more point mutations in the BTK gene. In one embodiment, the one or more point mutations in the BTK gene are translation of a BTK protein having one or more amino acid substitutions at one or more of the following amino acid positions: 117, 316, 474, 481, 528, 560, 562 and 601 Causes. In one embodiment, the one or more point mutations in the BTK gene are one of the following amino acid substitutions: T117P, T316A, T474I, T474M, T474S, C481S, C481F, C481T, C481G, C481R, L528W, P560L, R562W, R562G and F601L Induces the translation of the abnormal BTK protein.

The present invention comprises the steps of: (a) detecting a dysregulation of the expression or activity or level of a BCR signaling pathway gene, a BCR signaling pathway protein, or any of these; And (b) administering a spray-dried dispersion, pharmaceutical composition or a therapeutically effective amount of a compound of formula I to a subject in need thereof. Provides a way to do it. In one embodiment, the subject has dysregulation of the expression or activity or level of a BCR signaling pathway gene, a BCR signaling pathway protein, or any of these. In one embodiment, the step of determining whether the cancer in the subject is a BTK-associated cancer comprises regulating the expression or activity or level of a BCR signaling pathway gene, a BCR signaling pathway protein, or any of these in a sample from the subject. And performing an assay for detecting an abnormality, and further comprising obtaining a sample from the subject. In one embodiment, the sample is a biopsy sample. In one embodiment, the assay is selected from the group consisting of sequencing, immunohistochemistry, enzyme-linked immunosorbent assay, and fluorescence in situ hybridization (FISH). In one embodiment, the FISH is a degraded FISH assay. In one embodiment, sequencing is pyrosequencing or next generation sequencing. In one embodiment, the BCR signaling pathway gene or BCR signaling pathway protein is selected from the group consisting of Cyclin-D1, CARD11, CD79B, CD79A, MYD88, and combinations thereof. In one embodiment, the dysregulation in the expression or activity or level of a BCR signaling pathway gene, a BCR signaling pathway protein, or any one of them is the result of one or more genetic alterations. In one embodiment, the one or more genetic alterations consist of chromosomal translocation t(11;14)(q13;q32), deletion of chromosome region 17p13, deletion of chromosome region 11q23, deletion of chromosome region 13q14 and trisomy of chromosome 12. Is selected from the group. In one embodiment, the one or more genetic alterations are one or more point mutations in a gene encoding a BCR signaling pathway protein. In one embodiment, the one or more point mutations in the gene encoding the BCR signaling pathway protein results in translation of the BCR signaling pathway protein with one or more amino acid substitutions, wherein the BCR signaling pathway protein is CARD11, CD79B, CD79A, MYD88 and combinations thereof. In one embodiment, BCR signaling to the one or more point mutations in the gene encoding the channel protein amino acid positions: results in a translation of MYD88 BCR signaling pathway protein having one or more amino acid substitution in at least one of ^L265. In one embodiment, the amino acid substitution is MYD88 ^L265P .

In one embodiment, the BTK-associated cancer is Hodgkin's lymphoma, diffuse large B cell lymphoma (DLBCL) (e.g., activated B cell-like DLBCL (ABC-DLBCL)), follicular lymphoma, mantle cell lymphoma, marginal zone Lymphoma (e.g., extranodal marginal B-cell lymphoma, splenic marginal lymphoma), Burkitt's lymphoma, Waldenstrom's macroglobulinemia (lymphocyte lymphoma (LPL)), primary central nervous system lymphoma, small lymphocytic lymphoma, chronic lymphocytic Leukemia (CLL), acute lymphocytic leukemia (ALL), B-cell prolymphocytic leukemia, precursor B-lymphoblastic leukemia, hairy cell leukemia, acute myelogenous leukemia (AML), chronic myelogenous leukemia, multiple myeloma, plasma cells Myeloma, plasmacytoma, bone cancer, bone metastasis, breast cancer, gastroesophageal cancer, pancreatic cancer, ovarian cancer, prostate cancer, lung cancer, colon cancer, uterine cancer, hepatocellular cancer, head and neck cancer, or glioma.

In one embodiment, the BTK-associated cancer is a hematological cancer. In one embodiment, the hematologic cancer is selected from the group consisting of leukemia, lymphoma (non-Hodgkin's lymphoma), Hodgkin's disease and myeloma. In one embodiment, the hematologic cancer is acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myelocytic leukemia (CML). Sexual leukemia (CMML), chronic neutrophilic leukemia (CNL), acute undifferentiated leukemia (AUL), anaplastic large cell lymphoma (ALCL), prolymphocytic leukemia (PML), childhood myelomonocytic leukemia (JMML), adult T- Cell ALL, AML with line 3 myelodysplasia (AML/TMDS), mixed line leukemia (MLL), myelodysplastic syndrome (MDS), myeloproliferative disorder (MPD), diffuse versus B cell lymphoma (DLBCL) (e.g., Activated B cell-like DLBCL (ABC-DLBCL)), follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma (e.g., extranodal marginal zone B-cell lymphoma, spleen marginal zone lymphoma), Burkitt's lymphoma, Waldenstrom macroglobulinemia ( Lymphoblastic lymphoma (LPL)), primary central nervous system lymphoma, small lymphocytic lymphoma, precursor B-lymphoblastic leukemia, hairy cell leukemia, chronic myelogenous leukemia, anaplastic large cell lymphoma, MALT lymphoma, plasma cell myeloma, Plasmacytoma and multiple myeloma (MM).

In one embodiment, the BTK-associated cancer is a B-cell malignancy. In one embodiment, the B-cell malignancies are Hodgkin's lymphoma, diffuse large B cell lymphoma (DLBCL) (e.g., activated B cell-like DLBCL (ABC-DLBCL)), follicular lymphoma, mantle cell lymphoma, Marginal zone lymphoma (e.g., extranodal marginal B-cell lymphoma, splenic marginal zone lymphoma), Burkitt's lymphoma, Waldenstrom macroglobulinemia (Lymphplasmocytic lymphoma (LPL)), primary central nervous system lymphoma, small lymphocytic lymphoma, chronic lymph Constituent leukemia, acute lymphoblastic leukemia (ALL), B-cell prolymphocytic leukemia, precursor B-lymphoblastic leukemia or hairy cell leukemia.

In one embodiment, the BTK-associated cancer is selected from the group consisting of mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstrom macroglobulinemia, and marginal zone lymphoma. In one embodiment, the BTK-associated cancer is a solid tumor. In one embodiment, the solid tumor is selected from the group consisting of bone cancer, bone metastasis, breast cancer, gastroesophageal cancer, pancreatic cancer, ovarian cancer, prostate cancer, lung cancer, colon cancer, uterine cancer, hepatocellular cancer, head and neck cancer, and glioma.

The invention further comprises administering to the subject an additional therapy or therapeutic agent. In one embodiment, the additional therapy or therapeutic agent is selected from radiotherapy, cytotoxic chemotherapeutic agents, kinase-targeted therapeutic agents, apoptosis modulators, signal transduction inhibitors, immune-targeting therapy, transcription control inhibitors, and angiogenesis-targeting therapy. In one embodiment, the additional therapeutic agent is selected from one or more kinase-targeted therapeutic agents. In one embodiment, the kinase-targeting therapeutic agent targets a kinase from a kinase family selected from JAK, Src, IRAK, and combinations thereof. In one embodiment, the additional therapeutic agent is a protein selected from the group consisting of anti-apoptotic protein, heat shock protein, nuclear efflux protein, kinase, histone deacetylase, E3 ubiquitin ligase, histone-lysine N-methyltransferase, and combinations thereof. Suppress. In one embodiment, the additional therapeutic agent is PI3K, JAK-2, IRAK1, IRAK4, BMX, TAK1, Src family, HDAC6, MDM2, BCL-2, EZH2, EHMT2, PIM, JAK3, mTOR, ROR-1, Syk, Inhibits a protein selected from the group consisting of PKC, Hsp90, XPO1 and combinations thereof. In one embodiment, the additional therapeutic agent(s) are administered simultaneously as separate dosages. In one embodiment, the additional therapeutic agent(s) are administered sequentially in any order as individual dosages.

The present invention provides the steps of (a) administering to a subject having cancer at least one dose of a first BTK inhibitor for a predetermined period of time; (b) After (a), the cancer cells in the sample obtained from the subject have at least one BTK inhibitor resistance mutation that confers to the cancer cells or tumors increased resistance to treatment with the first BTK inhibitor of step (a). Determining whether to have; And (c) when the subject has cancer cells with at least one BTK inhibitor resistance mutation conferring increased resistance to treatment with the first BTK inhibitor of step (a) to the cancer cells or tumors, Administering the composition as monotherapy or with another anticancer agent; Or (d) if the subject has cancer cells that do not have a BTK inhibitor resistance mutation conferring increased resistance to treatment with the first BTK inhibitor of step (a) to the cancer cells or tumors, the subject is given step (a) ) Administering an additional dose of the first BTK inhibitor. In one embodiment, the anticancer agent in step (c) is a second BTK inhibitor, immunotherapy, or a combination thereof. In one embodiment, the anticancer agent in step (c) is the first BTK inhibitor administered in step (a). In one embodiment, the anticancer agent in step (c) is selected from one or more kinase-targeted therapeutic agents. In one embodiment, the kinase-targeting therapeutic agent targets a kinase from a kinase family selected from JAK, Src, IRAK, and combinations thereof. In one embodiment, the anticancer agent in step (c) consists of anti-apoptotic protein, heat shock protein, nuclear efflux protein, kinase, histone deacetylase, E3 ubiquitin ligase, histone-lysine N-methyltransferase, and combinations thereof. It is a protein inhibitor that inhibits a protein selected from the group. In one embodiment, the protein inhibitor is PI3K, JAK-2, IRAK1, IRAK4, BMX, TAK1, Src family, HDAC6, MDM2, BCL-2, EZH2, EHMT2, PIM, JAK3, mTOR, ROR-1, Syk, PKC , Hsp90, XPO1 and combinations thereof. In one embodiment, the subject is administered an additional dose of the first BTK inhibitor of step (a), and the method further comprises (e) administering to the subject another anticancer agent. In one embodiment, the anticancer agent of step (e) is a second BTK inhibitor, immunotherapy, or a combination thereof. In one embodiment, the anticancer agent of step (e) is a spray-dried dispersion or pharmaceutical composition.

The present invention provides the steps of (a) administering to a subject having cancer at least one dose of a first BTK inhibitor for a predetermined period of time; (b) After (a), the cancer cells in the sample obtained from the subject have at least one BTK inhibitor resistance mutation that confers to the cancer cells or tumors increased resistance to treatment with the first BTK inhibitor of step (a). Determining whether to have; (c) if the subject has cancer cells with at least one BTK inhibitor resistance mutation conferring increased resistance to treatment with the first BTK inhibitor of step (a) to the cancer cell or tumor, the subject is given a second Administering a BTK inhibitor as monotherapy or in combination with another anticancer agent; Or (d) if the subject has cancer cells that do not have a BTK inhibitor resistance mutation conferring increased resistance to treatment with the first BTK inhibitor of step (a) to the cancer cells or tumors, the subject is given step (a) ) Administering an additional dose of a first BTK inhibitor, wherein the mutation is a substitution at amino acid position 481, e.g. C481S, C481F, C481T, C481G and C481R. Provides. In one embodiment, the anticancer agent of step (c) is the first BTK inhibitor administered in step (a). In one embodiment, the subject is administered an additional dose of the first BTK inhibitor of step (a), and the method further comprises (e) administering another anticancer agent. In one embodiment, the anticancer agent of step (e) is a second BTK inhibitor, immunotherapy, or a combination thereof. In one embodiment, the anticancer agent of step (e) is a pharmaceutical composition as described herein or a pharmaceutically acceptable salt thereof.

The present invention provides the steps of (a) administering to a subject having cancer at least one dose of a first BTK inhibitor for a predetermined period of time; (b) After (a), the cancer cells in the sample obtained from the subject have at least one BTK inhibitor resistance mutation that confers to the cancer cells or tumors increased resistance to treatment with the first BTK inhibitor of step (a). Determining whether to have; (c) if the subject has cancer cells with at least one BTK inhibitor resistance mutation that confers to the cancer cells or tumors increased resistance to treatment with the first BTK inhibitor of step (a), the subject is provided herein Administering a spray-dried dispersion as described or a pharmaceutical composition as described herein as monotherapy or with another anticancer agent; Or (d) if the subject has cancer cells that do not have a BTK inhibitor resistance mutation conferring increased resistance to treatment with the first BTK inhibitor of step (a) to the cancer cells or tumors, the subject is given step (a) ) Administering an additional dose of a first BTK inhibitor, wherein the mutation is at one or more amino acid positions 244, 257, 334, 495, 664, 665, 707, 708, 742, 845, 848, of PLCγ2. A method of treating a subject having cancer, which is a substitution at 993, 1140 or 1141. In one embodiment, the anticancer agent of step (c) is selected from one or more kinase-targeted therapeutic agents. In one embodiment, the kinase-targeting therapeutic agent targets a kinase from a kinase family selected from JAK, Src, IRAK, and combinations thereof. In one embodiment, the anticancer agent in step (c) consists of anti-apoptotic protein, heat shock protein, nuclear efflux protein, kinase, histone deacetylase, E3 ubiquitin ligase, histone-lysine N-methyltransferase, and combinations thereof. It is a protein inhibitor that inhibits a protein selected from the group. In one embodiment, the protein inhibitor is PI3K, JAK-2, IRAK1, IRAK4, BMX, TAK1, Src family, HDAC6, MDM2, BCL-2, EZH2, EHMT2, PIM, JAK3, mTOR, ROR-1, Syk, PKC , Hsp90, XPO1 and combinations thereof.

The present invention provides an increase in the number of cancer cells in a sample obtained from a subject having (a) cancer and previously administered at least one dose of a first BTK inhibitor to treatment with a first BTK inhibitor previously administered to the subject. Determining whether it has one or more BTK inhibitor resistance mutations that confer the increased resistance to the cancer cells or tumors; And (b) if the subject has cancer cells with at least one BTK inhibitor resistance mutation that confers to the cancer cells or tumors increased resistance to treatment with a first BTK inhibitor previously administered to the subject, to the subject. Administering a spray-dried dispersion as described herein or a pharmaceutical composition as described herein as monotherapy or in combination with another anticancer agent; Or (c) when the subject has cancer cells or cancer cells that do not have a BTK inhibitor resistance mutation conferring increased resistance to treatment with a first BTK inhibitor previously administered to the subject, the subject is given a first Methods of treating a subject having cancer comprising administering an additional dose of a BTK inhibitor are provided. In one embodiment, the anticancer agent of step (b) is a second BTK inhibitor, immunotherapy, or a combination thereof. In one embodiment, the anticancer agent of step (b) is a first BTK inhibitor previously administered to the subject. In one embodiment, the anticancer agent in step (b) is selected from one or more kinase-targeted therapeutic agents. In one embodiment, the kinase-targeting therapeutic agent targets a kinase from a kinase family selected from JAK, Src, IRAK, and combinations thereof. In one embodiment, the anticancer agent in step (b) consists of anti-apoptotic protein, heat shock protein, nuclear efflux protein, kinase, histone deacetylase, E3 ubiquitin ligase, histone-lysine N-methyltransferase, and combinations thereof. It is a protein inhibitor that inhibits a protein selected from the group. In one embodiment, the protein inhibitor is PI3K, JAK-2, IRAK1, IRAK4, BMX, TAK1, Src family, HDAC6, MDM2, BCL-2, EZH2, EHMT2, PIM, JAK3, mTOR, ROR-1, Syk, PKC , Hsp90, XPO1 and combinations thereof. In one embodiment, the subject is administered an additional dose of a first BTK inhibitor previously administered to the subject, and the method further comprises (d) administering to the subject another anticancer agent. In one embodiment, the anticancer agent of step (d) is a second BTK inhibitor, immunotherapy, protein inhibitor, or a combination thereof. In one embodiment, the anticancer agent of step (d) is a spray-dried dispersion or pharmaceutical composition.

The present invention provides an increase in the number of cancer cells in a sample obtained from a subject having (a) cancer and previously administered at least one dose of a first BTK inhibitor to treatment with a first BTK inhibitor previously administered to the subject. Determining whether it has one or more BTK inhibitor resistance mutations that confer the increased resistance to the cancer cells or tumors; And (b) if the subject has cancer cells with at least one BTK inhibitor resistance mutation that confers to the cancer cells or tumors increased resistance to treatment with a first BTK inhibitor previously administered to the subject, to the subject. Administering to the subject a second BTK inhibitor as monotherapy or in combination with another anticancer agent; Or (c) if the subject has cancer cells that do not have a BTK inhibitor resistance mutation that confers to the cancer cells or tumors increased resistance to treatment with a first BTK inhibitor previously administered to the subject, It provides a method of treating a subject having cancer comprising administering an additional dose of the administered first BTK inhibitor. In one embodiment, the anticancer agent of step (b) is a first BTK inhibitor previously administered to the subject. In one embodiment, the subject is administered an additional dose of a first BTK inhibitor previously administered to the subject, and the method further comprises (d) administering to the subject another anticancer agent.

The present invention comprises the steps of: (a) administering at least one dose of the spray-dried dispersion or pharmaceutical composition over a period of time; (b) after (a), at least one cancer cell in the sample obtained from the subject confers to the cancer cell or tumor increased resistance to treatment with the spray-dried dispersion or pharmaceutical composition of step (a). Determining whether or not it has a BTK inhibitor resistance mutation; And (c) the spray-dried dispersion or pharmaceutical composition of step (a) to a subject having cancer cells having one or more BTK inhibitor resistance mutations that confer increased resistance to treatment with the cancer cells or tumors. 2 administering a BTK inhibitor as monotherapy or in combination with another anticancer agent; Or (d) a spray-dried dispersion to a subject having cancer cells that do not have a BTK inhibitor resistance mutation that confers increased resistance to treatment with the spray-dried dispersion of step (a) to the cancer cells or tumors. Or administering an additional dose of the pharmaceutical composition. In one embodiment, the anticancer agent of step (c) is a first BTK inhibitor, immunotherapy, or a combination thereof. In one embodiment, the anticancer agent of step (c) is a spray-dried dispersion or pharmaceutical composition administered in step (a). In one embodiment, the subject is administered an additional dose of the spray-dried dispersion or pharmaceutical composition of step (a), and the method further comprises (e) administering another anticancer agent to the subject. In one embodiment, the anticancer agent of step (e) is a second BTK inhibitor, immunotherapy, or a combination thereof.

The present invention comprises (a) cancer cells in a sample obtained from a subject having cancer and previously administered one or more doses of a spray-dried dispersion or pharmaceutical composition, a spray-dried dispersion previously administered to the subject. Determining whether it has one or more BTK inhibitor resistance mutations that confer to the cancer cells or tumors increased resistance to treatment with water or pharmaceutical compositions; (b) to a subject having cancer cells with one or more BTK inhibitor resistance mutations that confer to the cancer cells or tumors increased resistance to treatment with a spray-dried dispersion or pharmaceutical composition previously administered to the subject. 2 administering a BTK inhibitor as monotherapy or in combination with another anticancer agent; Or (c) previously administered to a subject with cancer cells that do not have a BTK inhibitor resistance mutation that confers increased resistance to treatment with a spray-dried dispersion or pharmaceutical composition previously administered to the subject. A method of treating a subject having cancer is provided, comprising administering an additional dose of the administered spray-dried dispersion or pharmaceutical composition. In one embodiment, the anticancer agent of step (b) is a second BTK inhibitor, immunotherapy, or a combination thereof. In one embodiment, the anticancer agent of step (b) is a spray-dried dispersion or pharmaceutical composition previously administered to a subject. In one embodiment, the subject is administered an additional dose of a spray-dried dispersion or pharmaceutical composition previously administered to the subject, and the method further comprises (d) administering another anticancer agent to the subject. In one embodiment, the anticancer agent of step (d) is a second BTK inhibitor, immunotherapy, or a combination thereof.

The present invention provides the steps of: (a) administering one or more doses of the spray-dried dispersion or pharmaceutical composition as monotherapy to a subject identified or diagnosed with BTK-associated cancer; (b) after step (a), determining the level of circulating tumor DNA in the biological sample obtained from the subject; (c) administering a spray-dried dispersion or pharmaceutical composition and an additional therapeutic agent or treatment to a subject identified as having approximately the same or elevated levels of circulating tumor DNA compared to a reference level of circulating tumor DNA. Wherein the additional therapeutic agent is a second BTK kinase inhibitor, providing a method of treating BTK-associated cancer in a subject. In one embodiment, the additional therapeutic agent or treatment comprises one or more of radiation therapy, chemotherapeutic agents, checkpoint inhibitors, surgery, and one or more second kinase inhibitors. In one embodiment, the reference level of circulating tumor DNA is the level of circulating tumor DNA in a biological sample obtained from a subject prior to step (a).

The present invention is (i) identified or diagnosed as having BTK-associated cancer, (ii) previously administered at least one dose of the spray-dried dispersion or pharmaceutical composition as monotherapy, and (ii) at least one After administration of a dose of spray-dried dispersion or pharmaceutical composition as monotherapy, spray-drying of a therapeutically effective amount to a subject identified as having approximately the same or elevated levels of circulating tumor DNA compared to the reference level of circulating tumor DNA. A method of treating BTK-associated cancer in a subject comprising administering the resulting dispersion or pharmaceutical composition and an additional therapeutic agent or treatment. In one embodiment, the reference level of circulating tumor DNA is the level of circulating tumor DNA in a biological sample obtained from a subject prior to administration of one or more doses of a spray-dried dispersion or pharmaceutical composition as monotherapy. In one embodiment, the additional therapeutic agent is a second BTK kinase inhibitor. In one embodiment, the additional therapeutic agent or treatment comprises one or more of radiation therapy, chemotherapeutic agents, checkpoint inhibitors, surgery, and one or more second protein inhibitors.

The present invention is (i) identified or diagnosed as having a BTK-associated cancer, (ii) previously administered at least one dose of a second BTK kinase inhibitor, and (ii) at least one dose of a second BTK kinase inhibitor. After administration of the circulating tumor DNA, selecting a therapeutically effective amount of a spray-dried dispersion or pharmaceutical composition for a subject identified as having an approximately equal or elevated level of circulating tumor DNA compared to a reference level of circulating tumor DNA. , Provides a method of selecting a treatment for a subject. In one embodiment, the reference level of circulating tumor DNA is the level of circulating tumor DNA in a biological sample obtained from a subject prior to administration of one or more doses of a second BTK kinase inhibitor.

The present invention is (i) identified or diagnosed as having BTK-associated cancer, (ii) previously administered at least one dose of the spray-dried dispersion or pharmaceutical composition as monotherapy, and (ii) at least one After administration of a dose of spray-dried dispersion or pharmaceutical composition, a therapeutically effective amount of spray-dried dispersion for subjects identified as having approximately the same or elevated levels of circulating tumor DNA compared to a reference level of circulating tumor DNA. A method of selecting a treatment for a subject is provided, comprising the step of selecting water or a pharmaceutical composition and an additional therapeutic treatment. In one embodiment, the reference level of circulating tumor DNA is in a biological sample obtained from a subject prior to administration of one or more doses of a spray-dried dispersion as described herein or a pharmaceutical composition as described herein as monotherapy. Is the level of circulating tumor DNA. In one embodiment, the additional therapeutic treatment is a second BTK kinase inhibitor. In one embodiment, the additional therapeutic treatment comprises one or more of radiation therapy, chemotherapeutic agents, checkpoint inhibitors, and one or more second protein inhibitors.

The present invention comprises the steps of: (a) determining a first level of circulating tumor DNA in a biological sample obtained from a subject identified or diagnosed with a BTK-associated cancer at a first time point; (b) after the first time point and before the second time point, administering to the subject one or more doses of a spray-dried dispersion as described herein or a treatment comprising a pharmaceutical composition as described herein; (c) determining a second level of circulating tumor DNA in the biological sample obtained from the subject at a second time point; And (d) confirming that the treatment is effective in a subject determined to have a reduced second level of circulating tumor DNA compared to the first level of circulating tumor DNA; Or confirming that the treatment is not effective in a subject determined to have a second level of circulating tumor DNA that is approximately the same or elevated compared to the first level of circulating tumor DNA. Provides a way. In one embodiment, the first and second time points are about 1 week to about 1 year apart.

The present invention comprises the steps of: (a) determining a first level of circulating tumor DNA in a biological sample obtained from a subject identified or diagnosed with a BTK-associated cancer at a first time point; (b) after the first time point and before the second time point, administering to the subject a treatment comprising one or more doses of the spray-dried dispersion or pharmaceutical composition; (c) determining a second level of circulating tumor DNA in the biological sample obtained from the subject at a second time point; And (d) determining that a subject with a second level of circulating tumor DNA reduced compared to the first level of circulating tumor DNA has not developed resistance to treatment; Or determining that a subject with a second level of circulating tumor DNA that is approximately the same or elevated compared to the first level of circulating tumor DNA has developed resistance to treatment. Provides a way to determine whether or not. In one embodiment, the first and second time points are about 1 week to about 1 year apart.

The present invention provides the use of a spray-dried dispersion or pharmaceutical composition for the manufacture of a medicament for treating BTK-associated cancer in a subject. In one embodiment, the BTK-associated cancer is a cancer having dysregulation in the expression or activity or level of the BTK gene, BTK kinase protein, or any of these. In one embodiment, the dysregulation in the expression or activity or level of a BTK gene, a BTK kinase protein, or any of these is the expression or activity or level of a BCR signaling pathway gene, a BCR signaling pathway protein, or any of these. It is the result of an abnormality of regulation in In one embodiment, the BCR signaling pathway gene or BCR signaling pathway protein is selected from the group consisting of Cyclin-D1, CARD11, CD79B, CD79A, MYD88, and combinations thereof. In one embodiment, the dysregulation in the expression or activity or level of a BCR signaling pathway gene, a BCR signaling pathway protein, or any one of them is the result of one or more genetic alterations. In one embodiment, the one or more genetic alterations consist of chromosomal translocation t(11;14)(q13;q32), deletion of chromosome region 17p13, deletion of chromosome region 11q23, deletion of chromosome region 13q14 and trisomy of chromosome 12. Is selected from the group. In one embodiment, the one or more genetic alterations are one or more point mutations in a gene encoding a BCR signaling pathway protein. In one embodiment, the one or more point mutations in the gene encoding the BCR signaling pathway protein results in translation of the BCR signaling pathway protein with one or more amino acid substitutions, wherein the BCR signaling pathway protein is CARD11, CD79B, CD79A, MYD88 and combinations thereof. In one embodiment, BCR signaling pathway protein with one or more point mutations to the amino acid positions in the genes encoding: MYD88 results in a translation of BCR signaling pathway protein comprising the amino acid substitution at least one of the at least one of ^L265 . In one embodiment, the amino acid substitution is MYD88 ^L265P . In one embodiment, the dysregulation in the expression or activity or level of the BTK gene, BTK kinase protein, or any of these is one or more point mutations in the BTK gene. In one embodiment, the one or more point mutations in the BTK gene are translation of a BTK protein having one or more amino acid substitutions at one or more of the following amino acid positions: 117, 316, 474, 481, 528, 560, 562 and 601 Causes. In one embodiment, the one or more point mutations in the BTK gene are one of the following amino acid substitutions: T117P, T316A, T474I, T474M, T474S, C481S, C481F, C481T, C481G, C481R, L528W, P560L, R562W, R562G and F601L Induces the translation of the abnormal BTK protein.

In one embodiment, the BTK-associated cancer is Hodgkin's lymphoma, diffuse large B cell lymphoma (DLBCL) (e.g., activated B cell-like DLBCL (ABC-DLBCL)), follicular lymphoma, mantle cell lymphoma, marginal zone Lymphoma (e.g., extranodal marginal B-cell lymphoma, splenic marginal lymphoma), Burkitt's lymphoma, Waldenstrom's macroglobulinemia (lymphocyte lymphoma (LPL)), primary central nervous system lymphoma, small lymphocytic lymphoma, chronic lymphocytic Leukemia (CLL), acute lymphocytic leukemia (ALL), B-cell prolymphocytic leukemia, precursor B-lymphoblastic leukemia, hairy cell leukemia, acute myelogenous leukemia (AML), chronic myelogenous leukemia, multiple myeloma, plasma cells Myeloma, plasmacytoma, bone cancer, bone metastasis, breast cancer, gastroesophageal cancer, pancreatic cancer, ovarian cancer, prostate cancer, lung cancer, colon cancer, uterine cancer, hepatocellular cancer, head and neck cancer, or glioma.

In one embodiment, the BTK-associated cancer is a hematological cancer. In one embodiment, the hematologic cancer is selected from the group consisting of leukemia, lymphoma (non-Hodgkin's lymphoma), Hodgkin's disease and myeloma. In one embodiment, the hematologic cancer is acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myelocytic leukemia (CML). Sexual leukemia (CMML), chronic neutrophilic leukemia (CNL), acute undifferentiated leukemia (AUL), anaplastic large cell lymphoma (ALCL), prolymphocytic leukemia (PML), childhood myelomonocytic leukemia (JMML), adult T- Cell ALL, AML with line 3 myelodysplasia (AML/TMDS), mixed line leukemia (MLL), myelodysplastic syndrome (MDS), myeloproliferative disorder (MPD), diffuse versus B cell lymphoma (DLBCL) (e.g., Activated B cell-like DLBCL (ABC-DLBCL)), follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma (e.g., extranodal marginal zone B-cell lymphoma, spleen marginal zone lymphoma), Burkitt's lymphoma, Waldenstrom macroglobulinemia ( Lymphoblastic lymphoma (LPL)), primary central nervous system lymphoma, small lymphocytic lymphoma, precursor B-lymphoblastic leukemia, hairy cell leukemia, chronic myelogenous leukemia, anaplastic large cell lymphoma, MALT lymphoma, plasma cell myeloma, Plasmacytoma and multiple myeloma (MM).

In one embodiment, the BTK-associated cancer is a B-cell malignancy. In one embodiment, the cancer is a B-cell malignancy, which is Hodgkin's lymphoma, diffuse versus B cell lymphoma (DLBCL) (e.g., activated B cell-like DLBCL (ABC-DLBCL)), follicular lymphoma, Mantle cell lymphoma, marginal zone lymphoma (e.g., extranodal marginal B-cell lymphoma, splenic marginal zone lymphoma), Burkitt's lymphoma, Waldenstrom macroglobulinemia (Lymphplasmocytic lymphoma (LPL)), primary central nervous system lymphoma, small lymphocytic Lymphoma, chronic lymphocytic leukemia, acute lymphoblastic leukemia (ALL), B-cell prolymphocytic leukemia, precursor B-lymphoblastic leukemia or hairy cell leukemia.

In one embodiment, the BTK-associated cancer is selected from the group consisting of mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstrom macroglobulinemia, and marginal zone lymphoma.

In one embodiment, the BTK-associated cancer is a solid tumor. In one embodiment, the solid tumor is selected from the group consisting of bone cancer, bone metastasis, breast cancer, gastroesophageal cancer, pancreatic cancer, ovarian cancer, prostate cancer, lung cancer, colon cancer, uterine cancer, hepatocellular cancer, head and neck cancer, and glioma.

In one embodiment, the medicament is formulated for oral administration.

The present invention provides a spray-dried dispersion as described herein or a pharmaceutical composition as described herein for use in treating a subject identified or diagnosed with BTK-associated cancer. In one embodiment, the BTK-associated cancer is a cancer having dysregulation in the expression or activity or level of the BTK gene, BTK kinase protein, or any of these. In one embodiment, the dysregulation in the expression or activity or level of the BTK gene, BTK kinase protein, or any of these is one or more point mutations in the BTK gene. In one embodiment, the one or more point mutations in the BTK gene are translation of a BTK protein having one or more amino acid substitutions at one or more of the following amino acid positions: 117, 316, 474, 481, 528, 560, 562 and 601 Causes. In one embodiment, the one or more point mutations in the BTK gene are one of the following amino acid substitutions: T117P, T316A, T474I, T474M, T474S, C481S, C481F, C481T, C481G, C481R, L528W, P560L, R562W, R562G and F601L Induces the translation of the abnormal BTK protein.

In one embodiment, the dysregulation at the expression or activity or level of a BTK gene, a BTK kinase protein, or any of these, is the expression or activity or level of a BCR signaling pathway gene, a BCR signaling pathway protein, or any of these. It is an abnormality of regulation in

In one embodiment, the BCR signaling pathway gene or BCR signaling pathway protein is selected from the group consisting of Cyclin-D1, CARD11, CD79B, CD79A, MYD88, and combinations thereof. In one embodiment, the dysregulation in the expression or activity or level of a BCR signaling pathway gene, a BCR signaling pathway protein, or any one of them is the result of one or more genetic alterations.

In one embodiment, the one or more genetic alterations consist of chromosome translocation t(11;14)(q13;q32), deletion of chromosome region 17p13, deletion of chromosome region 11q23, deletion of chromosome region 13q14 and trisomy of chromosome 12. Is selected from the group. In one embodiment, the one or more genetic alterations are one or more point mutations in a gene encoding a BCR signaling pathway protein.

In one embodiment, at least one point mutation in the gene encoding the BCR signaling pathway protein results in translation of the BCR signaling pathway protein with at least one amino acid substitution, wherein the BCR signaling pathway protein is CARD11, CD79B, CD79A, MYD88 and combinations thereof. In one embodiment, BCR signaling to the one or more point mutations in the gene encoding the channel protein amino acid positions: results in a translation of MYD88 BCR signaling pathway protein having one or more amino acid substitution in at least one of ^L265.

In one embodiment, the amino acid substitution is MYD88 ^L265P .

In one embodiment, the BTK-associated cancer is Hodgkin's lymphoma, diffuse large B cell lymphoma (DLBCL) (e.g., activated B cell-like DLBCL (ABC-DLBCL)), follicular lymphoma, mantle cell lymphoma, marginal zone Lymphoma (e.g., extranodal marginal B-cell lymphoma, splenic marginal lymphoma), Burkitt's lymphoma, Waldenstrom's macroglobulinemia (lymphocyte lymphoma (LPL)), primary central nervous system lymphoma, small lymphocytic lymphoma, chronic lymphocytic Leukemia (CLL), acute lymphocytic leukemia (ALL), B-cell prolymphocytic leukemia, precursor B-lymphoblastic leukemia, hairy cell leukemia, acute myelogenous leukemia (AML), chronic myelogenous leukemia, multiple myeloma, plasma cells Myeloma, plasmacytoma, bone cancer, bone metastasis, breast cancer, gastroesophageal cancer, pancreatic cancer, ovarian cancer, prostate cancer, lung cancer, colon cancer, uterine cancer, hepatocellular cancer, head and neck cancer, or glioma.

In one embodiment, the BTK-associated cancer is a hematological cancer. In one embodiment, the hematologic cancer is selected from the group consisting of leukemia, lymphoma (non-Hodgkin's lymphoma), Hodgkin's disease and myeloma. In one embodiment, the hematologic cancer is acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myelocytic leukemia (CML). Sexual leukemia (CMML), chronic neutrophilic leukemia (CNL), acute undifferentiated leukemia (AUL), anaplastic large cell lymphoma (ALCL), prolymphocytic leukemia (PML), childhood myelomonocytic leukemia (JMML), adult T- Cell ALL, AML with line 3 myelodysplasia (AML/TMDS), mixed line leukemia (MLL), myelodysplastic syndrome (MDS), myeloproliferative disorder (MPD), diffuse versus B cell lymphoma (DLBCL) (e.g., Activated B cell-like DLBCL (ABC-DLBCL)), follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma (e.g., extranodal marginal zone B-cell lymphoma, spleen marginal zone lymphoma), Burkitt's lymphoma, Waldenstrom macroglobulinemia ( Lymphoblastic lymphoma (LPL)), primary central nervous system lymphoma, small lymphocytic lymphoma, precursor B-lymphoblastic leukemia, hairy cell leukemia, chronic myelogenous leukemia, anaplastic large cell lymphoma, MALT lymphoma, plasma cell myeloma, Plasmacytoma and multiple myeloma (MM).

In one embodiment, the BTK-associated cancer is a B-cell malignancy. In one embodiment, the cancer is a B-cell malignancy, which is Hodgkin's lymphoma, diffuse versus B cell lymphoma (DLBCL) (e.g., activated B cell-like DLBCL (ABC-DLBCL)), follicular lymphoma, Mantle cell lymphoma, marginal zone lymphoma (e.g., extranodal marginal B-cell lymphoma, splenic marginal zone lymphoma), Burkitt's lymphoma, Waldenstrom macroglobulinemia (Lymphplasmocytic lymphoma (LPL)), primary central nervous system lymphoma, small lymphocytic Lymphoma, chronic lymphocytic leukemia, acute lymphoblastic leukemia (ALL), B-cell prolymphocytic leukemia, precursor B-lymphoblastic leukemia or hairy cell leukemia.

In one embodiment, the BTK-associated cancer is selected from the group consisting of mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstrom macroglobulinemia, and marginal zone lymphoma.

In one embodiment, the BTK-associated cancer is a solid tumor. In one embodiment, the solid tumor is selected from the group consisting of bone cancer, bone metastasis, breast cancer, gastroesophageal cancer, pancreatic cancer, ovarian cancer, prostate cancer, lung cancer, colon cancer, uterine cancer, hepatocellular cancer, head and neck cancer, or glioma.

The present invention provides a method of inhibiting BTK kinase activity in a mammalian cell comprising contacting the mammalian cell with a spray-dried dispersion as described herein or a pharmaceutical composition as described herein. In one embodiment, the contacting takes place in vivo. In one embodiment, the contacting takes place in vitro.

In one embodiment, the mammalian cell is a mammalian cancer cell. In one embodiment, the mammalian cancer cell is a mammalian BTK-associated cancer cell. In one embodiment, the cell has a dysregulation of the expression or activity or level of the BTK gene, BTK kinase protein, or any of these. In one embodiment, the dysregulation in the expression or activity or level of the BTK gene, BTK kinase protein, or any of these is one or more point mutations in the BTK gene. In one embodiment, the one or more point mutations in the BTK gene have a BTK protein having one or more amino acid substitutions at one or more of the following amino acid positions: 117, 316, 474, 481, 495, 528, 560, 562 and 601 Triggers the translation of. In one embodiment, the one or more point mutations in the BTK gene are one of the following amino acid substitutions: T117P, T316A, T474I, T474M, T474S, C481S, C481F, C481T, C481G, C481R, L528W, P560L, R562W, R562G and F601L Induces the translation of the abnormal BTK protein.

In one embodiment, the dysregulation at the expression or activity or level of a BTK gene, a BTK kinase protein, or any of these, is the expression or activity or level of a BCR signaling pathway gene, a BCR signaling pathway protein, or any of these. It is the result of an abnormality of regulation. In one embodiment, the BCR signaling pathway gene or BCR signaling pathway protein is selected from the group consisting of Cyclin-D1, CARD11, CD79B, CD79A, MYD88, and combinations thereof. In one embodiment, the dysregulation in the expression or activity or level of a BCR signaling pathway gene, a BCR signaling pathway protein, or any one of them is the result of one or more genetic alterations.

In one embodiment, the one or more genetic alterations consist of chromosome translocation t(11;14)(q13;q32), deletion of chromosome region 17p13, deletion of chromosome region 11q23, deletion of chromosome region 13q14 and trisomy of chromosome 12. Is selected from the group.

In one embodiment, the one or more genetic alterations are one or more point mutations in a gene encoding a BCR signaling pathway protein. In one embodiment, at least one point mutation in the gene encoding the BCR signaling pathway protein results in translation of the BCR signaling pathway protein with at least one amino acid substitution, wherein the BCR signaling pathway protein is CARD11, CD79B, CD79A, MYD88 and combinations thereof. In one embodiment, BCR signaling to the one or more point mutations in the gene encoding the channel protein amino acid positions: results in a translation of MYD88 BCR signaling pathway protein having one or more amino acid substitution in at least one of ^L265. In one embodiment, the amino acid substitution is MYD88 ^L265P .

The present invention relates to administering to a subject a spray-dried dispersion as described herein or a pharmaceutical composition as described herein or a therapeutically effective amount of a compound according to formula (I) to a subject identified or diagnosed as having an autoimmune or inflammatory disease. It provides a method of treating an autoimmune or inflammatory disease in the subject, comprising the steps of. In one embodiment, the autoimmune or inflammatory disease is selected from the group consisting of rheumatoid arthritis, multiple sclerosis, osteoporosis, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, chronic urticaria, myasthenia gravis and systemic lupus erythematosus.

SEQUENCE LISTING <110> Eli Lilly and Company <120> Spray-dried dispersions, formulations, and polymorphs of (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-( 1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide <130> X22366 <150> US 62/712861 <151> 2018-07-31 <150> US 62/729855 <151> 2018-09-11 <150> US 62/769308 <151> 2018-11-19 <160> 1 <170> PatentIn version 3.5 <210> 1 <211> 659 <212> PRT <213> Homo sapiens <400> 1 Met Ala Ala Val Ile Leu Glu Ser Ile Phe Leu Lys Arg Ser Gln Gln 1 5 10 15 Lys Lys Lys Thr Ser Pro Leu Asn Phe Lys Lys Arg Leu Phe Leu Leu 20 25 30 Thr Val His Lys Leu Ser Tyr Tyr Glu Tyr Asp Phe Glu Arg Gly Arg 35 40 45 Arg Gly Ser Lys Lys Gly Ser Ile Asp Val Glu Lys Ile Thr Cys Val 50 55 60 Glu Thr Val Val Pro Glu Lys Asn Pro Pro Pro Glu Arg Gln Ile Pro 65 70 75 80 Arg Arg Gly Glu Glu Ser Ser Glu Met Glu Gln Ile Ser Ile Ile Glu 85 90 95 Arg Phe Pro Tyr Pro Phe Gln Val Val Tyr Asp Glu Gly Pro Leu Tyr 100 105 110 Val Phe Ser Pro Thr Glu Glu Leu Arg Lys Arg Trp Ile His Gln Leu 115 120 125 Lys Asn Val Ile Arg Tyr Asn Ser Asp Leu Val Gln Lys Tyr His Pro 130 135 140 Cys Phe Trp Ile Asp Gly Gln Tyr Leu Cys Cys Ser Gln Thr Ala Lys 145 150 155 160 Asn Ala Met Gly Cys Gln Ile Leu Glu Asn Arg Asn Gly Ser Leu Lys 165 170 175 Pro Gly Ser Ser His Arg Lys Thr Lys Lys Pro Leu Pro Pro Thr Pro 180 185 190 Glu Glu Asp Gln Ile Leu Lys Lys Pro Leu Pro Pro Glu Pro Ala Ala 195 200 205 Ala Pro Val Ser Thr Ser Glu Leu Lys Lys Val Val Ala Leu Tyr Asp 210 215 220 Tyr Met Pro Met Asn Ala Asn Asp Leu Gln Leu Arg Lys Gly Asp Glu 225 230 235 240 Tyr Phe Ile Leu Glu Glu Ser Asn Leu Pro Trp Trp Arg Ala Arg Asp 245 250 255 Lys Asn Gly Gln Glu Gly Tyr Ile Pro Ser Asn Tyr Val Thr Glu Ala 260 265 270 Glu Asp Ser Ile Glu Met Tyr Glu Trp Tyr Ser Lys His Met Thr Arg 275 280 285 Ser Gln Ala Glu Gln Leu Leu Lys Gln Glu Gly Lys Glu Gly Gly Phe 290 295 300 Ile Val Arg Asp Ser Ser Lys Ala Gly Lys Tyr Thr Val Ser Val Phe 305 310 315 320 Ala Lys Ser Thr Gly Asp Pro Gln Gly Val Ile Arg His Tyr Val Val 325 330 335 Cys Ser Thr Pro Gln Ser Gln Tyr Tyr Leu Ala Glu Lys His Leu Phe 340 345 350 Ser Thr Ile Pro Glu Leu Ile Asn Tyr His Gln His Asn Ser Ala Gly 355 360 365 Leu Ile Ser Arg Leu Lys Tyr Pro Val Ser Gln Gln Asn Lys Asn Ala 370 375 380 Pro Ser Thr Ala Gly Leu Gly Tyr Gly Ser Trp Glu Ile Asp Pro Lys 385 390 395 400 Asp Leu Thr Phe Leu Lys Glu Leu Gly Thr Gly Gln Phe Gly Val Val 405 410 415 Lys Tyr Gly Lys Trp Arg Gly Gln Tyr Asp Val Ala Ile Lys Met Ile 420 425 430 Lys Glu Gly Ser Met Ser Glu Asp Glu Phe Ile Glu Glu Ala Lys Val 435 440 445 Met Met Asn Leu Ser His Glu Lys Leu Val Gln Leu Tyr Gly Val Cys 450 455 460 Thr Lys Gln Arg Pro Ile Phe Ile Ile Thr Glu Tyr Met Ala Asn Gly 465 470 475 480 Cys Leu Leu Asn Tyr Leu Arg Glu Met Arg His Arg Phe Gln Thr Gln 485 490 495 Gln Leu Leu Glu Met Cys Lys Asp Val Cys Glu Ala Met Glu Tyr Leu 500 505 510 Glu Ser Lys Gln Phe Leu His Arg Asp Leu Ala Ala Arg Asn Cys Leu 515 520 525 Val Asn Asp Gln Gly Val Val Lys Val Ser Asp Phe Gly Leu Ser Arg 530 535 540 Tyr Val Leu Asp Asp Glu Tyr Thr Ser Ser Val Gly Ser Lys Phe Pro 545 550 555 560 Val Arg Trp Ser Pro Pro Glu Val Leu Met Tyr Ser Lys Phe Ser Ser 565 570 575 Lys Ser Asp Ile Trp Ala Phe Gly Val Leu Met Trp Glu Ile Tyr Ser 580 585 590 Leu Gly Lys Met Pro Tyr Glu Arg Phe Thr Asn Ser Glu Thr Ala Glu 595 600 605 His Ile Ala Gln Gly Leu Arg Leu Tyr Arg Pro His Leu Ala Ser Glu 610 615 620 Lys Val Tyr Thr Ile Met Tyr Ser Cys Trp His Glu Lys Ala Asp Glu 625 630 635 640 Arg Pro Thr Phe Lys Ile Leu Leu Ser Asn Ile Leu Asp Val Met Asp 645 650 655 Glu Glu Ser

Claims (19)

A compound of formula I present in an amount from about 5% w/w to about 30% w/w;

HPMCAS polymer present in an amount from about 5% w/w to about 30% w/w;
Microcrystalline cellulose present in an amount from about 30% w/w to about 60% w/w;
Mannitol or lactose monohydrate, or a combination thereof, present in a total amount of about 10% w/w to about 60% w/w;
Sodium starch glycolate or croscarmellose sodium or a combination thereof present in a total amount of about 0.5% w/w to about 5% w/w;
Magnesium stearate present in an amount from about 0.05% w/w to about 2% w/w; And
Optionally, if present, silicon dioxide in an amount from about 0.3% w/w to about 0.6% w/w.
A pharmaceutical composition comprising, wherein the total is 100% or less. The method of claim 1,
A compound of formula I present in an amount from about 5% w/w to about 30% w/w;
HPMCAS polymer present in an amount from about 5% w/w to about 30% w/w;
Microcrystalline cellulose present in an amount from about 30% w/w to about 60% w/w;
Lactose monohydrate present in an amount from about 10% w/w to about 60% w/w;
Croscarmellose sodium present in a total amount of about 0.5% w/w to about 5% w/w;
Magnesium stearate present in an amount from about 0.05% w/w to about 2% w/w; And
If present, silicon dioxide in an amount of about 0.3% w/w to about 0.6% w/w
A pharmaceutical composition comprising, wherein the total is 100% or less. The pharmaceutical composition of claim 1 or 2, wherein the ratio of the compound of formula (I) to the HPMCAS polymer is from about 1:4 to about 4:1. 4. The pharmaceutical composition of any one of claims 1-3, wherein the ratio of the compound of formula I to the HPMCAS polymer is about 1:1. The method of claim 1,
A compound of formula I present in an amount from about 21% w/w to about 23% w/w;
HPMCAS polymer present in an amount from about 21% w/w to about 23% w/w;
Microcrystalline cellulose present in an amount from about 38% w/w to about 39% w/w;
Mannitol present in an amount from about 12% w/w to about 13% w/w;
Sodium starch glycolate present in an amount from about 4% w/w to about 6% w/w; And
Magnesium stearate present in an amount from about 0.4% w/w to about 0.6% w/w
A pharmaceutical composition comprising, wherein the total is 100% or less. The method of claim 1,
A compound of formula I present in an amount from about 21% w/w to about 23% w/w;
HPMCAS polymer present in an amount from about 21% w/w to about 23% w/w;
Microcrystalline cellulose present in an amount from about 33% w/w to about 34% w/w;
Lactose monohydrate present in an amount from about 16% w/w to about 17% w/w;
Croscarmellose sodium present in an amount from about 2% w/w to about 6% w/w;
Magnesium stearate present in an amount from about 0.4% w/w to about 0.6% w/w; And
Silicon dioxide present in an amount of about 0.4% w/w to about 0.6% w/w
A pharmaceutical composition comprising, wherein the total is 100% or less. The method of claim 1,
A compound of formula I present in an amount from about 21% w/w to about 23% w/w;
HPMCAS polymer present in an amount from about 21% w/w to about 23% w/w;
Microcrystalline cellulose present in an amount from about 25% w/w to about 26% w/w;
Mannitol present in an amount from about 25% w/w to about 26% w/w;
Sodium starch glycolate present in an amount from about 4% w/w to about 6% w/w; And
Magnesium stearate present in an amount from about 0.4% w/w to about 0.6% w/w
A pharmaceutical composition comprising, wherein the total is 100% or less. The method of claim 1,
A compound of formula I present in an amount of about 8% w/w;
HPMCAS polymer present in an amount of about 8% w/w;
Microcrystalline cellulose present in an amount of about 40% w/w;
Mannitol present in an amount of about 40% w/w;
Sodium starch glycolate present in an amount of about 3.5% w/w; And
Magnesium stearate present in an amount of about 0.3% w/w
Pharmaceutical composition comprising a. The pharmaceutical composition according to any one of claims 1 to 8, formulated as a tablet. The pharmaceutical composition of any one of claims 1 to 9 comprising from about 25 mg to about 220 mg of a compound of formula (I). The pharmaceutical composition of claim 10 comprising a compound of formula I in an amount selected from the group consisting of about 25 mg, about 50 mg and about 100 mg. BTK-associated in a subject in need of treatment for BTK-associated cancer, comprising administering a pharmaceutical composition according to any one of claims 1 to 11 to a subject in need of treatment for BTK-associated cancer. How to cure cancer. The method of claim 12, wherein the BTK-associated cancer is selected from the group consisting of mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstrom macroglobulinemia, and marginal zone lymphoma. Administering to a subject in need of treatment of cancer a compound of formula I at a dose of about 20 mg to about 120 mg, wherein the cancer is mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstrom A method of treating cancer in a subject in need thereof, which is selected from the group consisting of macroglobulinemia and marginal zone lymphoma.

The method of claim 14, wherein the dose is selected from the group consisting of about 25 mg, about 50 mg and about 100 mg. Use of a compound of formula I for the treatment of BTK-associated cancer in a subject, wherein the BTK-associated cancer is from the group consisting of mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstrom macroglobulinemia, and marginal zone lymphoma. And the compound is administered in a dose of about 20 mg to about 120 mg.

Claims 1 to 9 for the treatment of BTK-associated cancers selected from the group consisting of mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstrom macroglobulinemia and marginal zone lymphoma at a dose of about 20 mg to 120 mg. Use of the pharmaceutical composition according to any one of the preceding claims. The method according to any one of claims 1 to 10, for use in the treatment of BTK-associated cancer selected from the group consisting of mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstrom macroglobulinemia, and marginal zone lymphoma. Pharmaceutical composition for. The use of any one of claims 16-18, wherein the dose is selected from the group consisting of about 25 mg, about 50 mg and about 100 mg.

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